A transcriptomic examination of encased rotifer embryos reveals the developmental trajectory leading to long-term dormancy; are they "animal seeds"?

BACKGROUND: Organisms from many distinct evolutionary lineages acquired the capacity to enter a dormant state in response to environmental conditions incompatible with maintaining normal life activities. Most studied organisms exhibit seasonal or annual episodes of dormancy, but numerous less studied organisms enter long-term dormancy, lasting decades or even centuries. Intriguingly, many planktonic animals produce encased embryos known as resting eggs or cysts that, like plant seeds, may remain dormant for decades. Herein, we studied a rotifer Brachionus plicatilis as a model planktonic species that forms encased dormant embryos via sexual reproduction and non-dormant embryos via asexual reproduction and raised the following questions: Which genes are expressed at which time points during embryogenesis? How do temporal transcript abundance profiles differ between the two types of embryos? When does the cell cycle arrest? How do dormant embryos manage energy? RESULTS: As the molecular developmental kinetics of encased embryos remain unknown, we employed single embryo RNA sequencing (CEL-seq) of samples collected during dormant and non-dormant embryogenesis. We identified comprehensive and temporal transcript abundance patterns of genes and their associated enriched functional pathways. Striking differences were uncovered between dormant and non-dormant embryos. In early development, the cell cycle-associated pathways were enriched in both embryo types but terminated with fewer nuclei in dormant embryos. As development progressed, the gene transcript abundance profiles became increasingly divergent between dormant and non-dormant embryos. Organogenesis was suspended in dormant embryos, concomitant with low transcript abundance of homeobox genes, and was replaced with an ATP-poor preparatory phase characterized by very high transcript abundance of genes encoding for hallmark dormancy proteins (e.g., LEA proteins, sHSP, and anti-ROS proteins, also found in plant seeds) and proteins involved in dormancy exit. Surprisingly, this period appeared analogous to the late maturation phase of plant seeds. CONCLUSIONS: The study highlights novel divergent temporal transcript abundance patterns between dormant and non-dormant embryos. Remarkably, several convergent functional solutions appear during the development of resting eggs and plant seeds, suggesting a similar preparatory phase for long-term dormancy. This study accentuated the broad novel molecular features of long-term dormancy in encased animal embryos that behave like "animal seeds".

Oxygenation in the NICU: there is more to it than meets the eye.

IMPACT: Dormishian and colleagues in their study address an issue that care teams in the NICU encounter on a daily basis, regarding motion artifacts during oxygenation monitoring. In our commentary, we discuss the available tools that allow continuous noninvasive monitoring of oxygenation in the NICU, and modalities that increase the time premature infants spend in the desired SpO2 range and impact their clinical outcomes.

Oxygen saturation histogram classification system to evaluate response to doxapram treatment in preterm infants.

BACKGROUND: An oxygen saturation (SpO2) histogram classification system has been shown to enable quantification of SpO2 instability into five types, based on histogram distribution and time spent at SpO2 ≤ 80%. We aimed to investigate this classification system as a tool to describe response to doxapram treatment in infants with severe apnea of prematurity. METHODS: This retrospective study included 61 very-low-birth-weight infants who received doxapram. SpO2 histograms were generated over the 24-h before and after doxapram start. Therapy response was defined as a decrease of ≥1 histogram types after therapy start. RESULTS: The median (IQR) histogram type decreased from 4 (3-4) before to 3 (2-3) after therapy start (p < 0.001). The median (IQR) FiO2 remained constant before (27% [24-35%]) and after (26% [22-35%]) therapy. Thirty-six infants (59%) responded to therapy within 24 h. In 34/36 (94%) of the responders, invasive mechanical ventilation (IMV) was not required during the first 72 h of therapy, compared to 15/25 (60%) of non-responders (p = 0.002). Positive and negative predictive values of the 24-h response for no IMV requirement within 72 h were 0.46 and 0.94, respectively. CONCLUSIONS: Classification of SpO2 histograms provides an objective bedside measure to assess response to doxapram therapy and can serve as a tool to detect changes in oxygenation status around respiratory interventions. IMPACT: The SpO2 histogram classification system provides a tool for quantifying response to doxapram therapy. The classification system allowed estimation of the probability of invasive mechanical ventilation requirement, already within a few hours of treatment. The SpO2 histogram classification system allows an objective bedside assessment of the oxygenation status of the preterm infant, making it possible to assess the changes in oxygenation status in response to respiratory interventions.

Oxygenation Instability during Bolus versus Continuous Feeding among Very Low Birth Weight Premature Infants, Supported by Noninvasive Ventilation: A Randomized Prospective Study.

OBJECTIVE: This study aimed to compare oxygenation instability, as documented by the oxygen saturation (SpO2) histograms, during bolus (over 30 minutes) versus continuous (over 2 hours) feeding among very low birth weight (VLBW) premature infants, supported with noninvasive ventilation (NIV). STUDY DESIGN: This was a randomized prospective study. VLBW infants supported with NIV received three consecutive feeds in a random order of bolus-continuous-bolus or continuous-bolus-continuous. During each feed, 30 minutes and 2 hours histograms were documented. RESULTS: Twenty-four infants (birth weight [mean ± standard deviation, SD] 820 ± 168 g, gestational age [mean ± SD] 27.0 ± 1.6 weeks) were included in our study (12 infants started with bolus feeding and 12 with continuous feeding) and 72 histograms were obtained (36 during bolus feeding and 36 during continuous feeding). No differences in mean fraction of inspired oxygen (FiO2), and number of apnea events were observed between the two feeding modes. Oxygenation instability as assessed by time spent in different SpO2 ranges and histogram types (stable or unstable) was comparable during bolus and continuous feedings. Changing feeding mode from bolus to continuous or vice versa did not significantly change the oxygenation instability of the group, though individual infants did show a consistence response to feeding length changes. CONCLUSION: Among VLBW infants supported with NIV, oxygenation instability, as documented by SpO2 histograms, was comparable between bolus and continuous feedings. Individual infants may benefit from specific feeding length, and this can be easily demonstrated by the SpO2 histograms. KEY POINTS: · Feeding length did not affect oxygenation instability of preterm infants on noninvasive respiratory Support.. · Oxygen saturation histograms allow objective quantification of oxygenation instability at the bedside.. · Individual infants benefit from specific feeding length, as demonstrated by SpO2 histograms..

The Molecular Mechanisms Employed by the Parasite Myxobolus bejeranoi (Cnidaria: Myxozoa) from Invasion through Sporulation for Successful Proliferation in Its Fish Host.

Myxozoa is a unique group of obligate endoparasites in the phylum Cnidaria that can cause emerging diseases in wild and cultured fish populations. Recently, we identified a new myxozoan species, Myxobolus bejeranoi, which infects the gills of cultured tilapia while suppressing host immunity. To uncover the molecular mechanisms underlying this successful parasitic strategy, we conducted transcriptomics analysis of M. bejeranoi throughout the infection. Our results show that histones, which are essential for accelerated cell division, are highly expressed even one day after invasion. As the infection progressed, conserved parasitic genes that are known to modulate the host immune reaction in different parasitic taxa were upregulated. These genes included energy-related glycolytic enzymes, as well as calreticulin, proteases, and miRNA biogenesis proteins. Interestingly, myxozoan calreticulin formed a distinct phylogenetic clade apart from other cnidarians, suggesting a possible function in parasite pathogenesis. Sporogenesis was in its final stages 20 days post-exposure, as spore-specific markers were highly expressed. Lastly, we provide the first catalog of transcription factors in a Myxozoa species, which is minimized compared to free-living cnidarians and is dominated by homeodomain types. Overall, these molecular insights into myxozoan infection support the concept that parasitic strategies are a result of convergent evolution.

Is there room for prompt routine ophthalmic examination in neonates with congenital cytomegalovirus (CMV) infection during the neonatal period?

PURPOSE: To establish the clinical necessity of routine targeted ophthalmic examination of newborns with congenital cytomegalovirus (CMV) infection during the neonatal period. METHODS: This retrospective study included consecutive neonates that were referred for ophthalmological screening within the context of a proven congenital CMV infection. The presence of CMV-related ocular and systemic findings was determined. RESULTS: Among the 91 patients included in this study, 72 (79.12%) were symptomatic with one or more of the following manifestations: abnormal brain ultrasound (42; 46.15%), small for gestational age (29; 31.87%), microcephaly (23; 25.27%), thrombocytopenia (14; 15.38%), sensory neural hearing loss (13; 14.29%), neutropenia (12; 13.19%), anemia (4; 4.4%), skin lesions (4; 4.4%), hepatomegaly (3; 3.3%), splenomegaly (3; 3.3%), direct hyperbilirubinemia (2; 2.2%). Not one single neonate in this cohort had any of the ocular findings surveyed. CONCLUSION: The presence of ophthalmological findings among neonates with congenital CMV infection during the neonatal period is infrequent, suggesting that routine ophthalmological screening may be safely deferred for the post-neonatal period.

Prenatal exposure to heavy metal mixtures and anthropometric birth outcomes: a cross-sectional study.

BACKGROUND: Numerous studies have suggested significant associations between prenatal exposure to heavy metals and newborn anthropometric measures. However, little is known about the effect of various heavy metal mixtures at relatively low concentrations. Hence, this study aimed to investigate associations between prenatal exposures to a wide range of individual heavy metals and heavy metal mixtures with anthropometric measures of newborns. METHODS: We recruited 975 mother-term infant pairs from two major hospitals in Israel. Associations between eight heavy metals (arsenic, cadmium, chromium, mercury, nickel, lead, selenium, and thallium) detected in maternal urine samples on the day of delivery with weight, length, and head circumference at birth were estimated using linear and Bayesian kernel machine regression (BKMR) models. RESULTS: Most heavy metals examined in our study were observed in lower concentrations than in other studies, except for selenium. In the linear as well as the BKMR models, birth weight and length were negatively associated with levels of chromium. Birth weight was found to be negatively associated with thallium and positively associated with nickel. CONCLUSION: By using a large sample size and advanced statistical models, we could examine the association between prenatal exposure to metals in relatively low concentrations and anthropometric measures of newborns. Chromium was suggested to be the most influential metal in the mixture, and its associations with birth weight and length were found negative. Head circumference was neither associated with any of the metals, yet the levels of metals detected in our sample were relatively low. The suggested associations should be further investigated and could shed light on complex biochemical processes involved in intrauterine fetal development.

Same baby, different care: variations in practice between neonatologists and pediatric intensivists.

The aim of the study was to identify and explore areas in neonatal care in which significant differences in clinical care exist, among neonatal intensive care (NICU) and pediatric intensive care (PICU) physicians. A questionnaire presenting three common scenarios in neonatal critical care-severe pneumonia, post-cardiac-surgery care, and congenital diaphragmatic hernia (CDH) was electronically sent to all PICU and NICU physicians in Israel. The survey was completed by 110 physicians. Significant differences were noted between NICU and PICU physicians' treatment choices. A non-cuffed endotracheal tube, initial high-frequency ventilation, and lower tidal volumes when applying synchronized-intermittent-mechanical-ventilation were selected more often by NICU physicians. For sedation/analgesia, NICU physicians treated as needed or by continuous infusion of a single agent, while PICU physicians more often chose to continuously infuse ≥ 2 medications. Fentanyl, midazolam, and muscle relaxants were chosen more often by PICU physicians. Morphine administration was similar for both groups. Treating CDH with pulmonary hypertension and systemic hypotension, NICU physicians more often began treatment with high dose dopamine and/or dobutamine, while PICU physicians chose low-dose adrenalin and/or milrinone. For vascular access NICU physicians chose umbilical lines most often, while PICU physicians preferred other central sites. CONCLUSION: Our study identified major differences in respiratory and hemodynamic care, sedation and analgesia, and vascular access between NICU and PICU physicians, resulting from field-specific consensus guidelines and practice traditions. We suggest to establish joint committees from both professions, aimed at finding the optimal treatment for this vulnerable population - be it in the NICU or in the PICU. WHAT IS KNOWN: • Variability in neonatal care between the neonatal and the pediatric intensive care units has been previously described. WHAT IS NEW: • This scenario-based survey study identified major differences in respiratory and hemodynamic care, sedation and analgesia, and vascular access between neonatologists and pediatric intensivists, resulting from lack of evidence-based literature to guide neonatal care, field-specific consensus guidelines, and practice traditions. • These findings indicate a need for joint committees, combining the unique skills and literature from both professions, to conduct clinical trials focusing on these specific areas of care, aimed at finding the optimal treatment for this vulnerable population - be it in the neonatal or the pediatric intensive care unit.

Continuous versus Bolus Gastric Tube Feeding in Very Low Birth Weight Infants Supported with Noninvasive Respiratory Support: A Randomized, Pilot Study.

OBJECTIVES: This study aimed to compare time to full feeding (TFF) between continuous gastric feeding (CGF) and bolus feeding (BF) in very low birth weight (VLBW) infants supported with noninvasive ventilation (NIV) and to evaluate feasibility and identify methodological pitfalls for future large-scale studies. STUDY DESIGN: This study is a randomized controlled, prospective, pilot study. VLBW premature infants, supported with NIV, were randomized while still on trophic feeding <20 mL/kg/day to receive feeding over 2 hours of CGF or over 15- to 30-minute BF. The primary outcome was TFF. Analysis was done by intention to treat. RESULTS: Overall, 32 infants were included in this analysis, 17 in the CGF group and 15 in the BF group. Infants in the CGF group were significantly younger than the BF group (mean ± standard deviation [SD] gestational age [GA] 26.9 ± 1.2 vs. 28.9 ± 1.5 weeks, respectively). TFF was comparable with median (interquartile range [IQR]) for the two groups, 10.0 (10.0, 19.0) days in the BF group versus 12.0 (9.0, 13.0) days in the CGF group (p = 0.59). Feeding length was not found to significantly affect TFF in multivariate analysis correcting for GA. Groups were comparable in weight gain, gastrointestinal complications, length of NIV, bronchopulmonary dysplasia incidence, and age at discharge. Most infants from both groups (60% of BF and 70% of CGF) required changes in feeding length. CONCLUSION: In this pilot study, among VLBW infants supported with NIV, TFF was comparable between the BF and CGF groups. These results should be interpreted with caution due to the small sample size and despite the multivariate analysis correcting for the different GA. Interestingly, most infants required changes in feeding length regardless of their allocation. This feasibility study emphasizes the need for careful attention to randomization and strict feeding protocols including criteria for switching allocation in future large-scale studies aimed at determining the preferred feeding length during NIV in VLBW infants. KEY POINTS: · Among infants supported with NIV, length of feeding affects gastric venting.. · BF might increase gastrointestinal reflux, while continuous feeding hinders gastric decompression.. · Among infants supported by NIV, feeding tolerance was comparable between bolus and continuous groups..

CTRP6 rapidly responds to acute nutritional changes, regulating adipose tissue expansion and inflammation in mice.

In chronic obesity, activated adipose tissue proinflammatory cascades are tightly linked to metabolic dysfunction. Yet, close temporal analyses of the responses to obesogenic environment such as high-fat feeding (HFF) in susceptible mouse strains question the causal relationship between inflammation and metabolic dysfunction, and/or raises the possibility that certain inflammatory cascades play adaptive/homeostatic, rather than pathogenic roles. Here, we hypothesized that CTRP6, a C1QTNF family member, may constitute an early responder to acute nutritional changes in adipose tissue, with potential physiological roles. Both 3-days high-fat feeding (3dHFF) and acute obesity reversal [2-wk switch to low-fat diet after 8-wk HFF (8wHFF)] already induced marked changes in whole body fuel utilization. Although adipose tissue expression of classical proinflammatory cytokines (Tnf-α, Ccl2, and Il1b) exhibited no, or only minor, change, C1qtnf6 uniquely increased, and decreased, in response to 3dHFF and acute obesity reversal, respectively. CTRP6 knockout (KO) mouse embryonic fibroblasts (MEFs) exhibited increased adipogenic gene expression (Pparg, Fabp4, and Adipoq) and markedly reduced inflammatory genes (Tnf-α, Ccl2, and Il6) compared with wild-type MEFs, and recombinant CTRP6 induced the opposite gene expression signature, as assessed by RNA sequencing. Consistently, 3dHFF of CTRP6-KO mice induced a greater whole body and adipose tissue weight gain compared with wild-type littermates. Collectively, we propose CTRP6 as a gene that rapidly responds to acute changes in caloric intake, acting in acute overnutrition to induce a "physiological inflammatory response" that limits adipose tissue expansion.NEW & NOTEWORTHY CTRP6 (C1qTNF6), a member of adiponectin gene family, regulates inflammation and metabolism in established obesity. Here, short-term high-fat feeding in mice is shown to increase adipose tissue expression of CTRP6 before changes in the expression of classical inflammatory genes occur. Conversely, CTRP6 expression in adipose tissue decreases early in the course of obesity reversal. Gain- and loss-of-function models suggest CTRP6 as a positive regulator of inflammatory cascades, and a negative regulator of adipogenesis and adipose tissue expansion.

Evaluation of audio-voice guided application for neonatal resuscitation: a prospective, randomized, pilot study.

OBJECTIVES: To examine whether audio-voice guidance application improves adherence to resuscitation sequence and recommended time frames during neonatal resuscitation. METHODS: A prospective, randomized, pilot study examining the use of an audio-voice application for guiding resuscitation on newborn mannequins, based on the Neonatal Resuscitation Program (NRP) algorithm. Two different scenarios, with and without voice guidance, were presented to 20 medical personnel (2 midwives, 8 nurses, and 10 physicians) in random order, and their performance videotaped. RESULTS: Audio-voice guided resuscitation compared with non-guided resuscitation, resulted in significantly better compliance with NRP order sequence (p<0.01), correct use of oxygen supplementation (p<0.01) and performance of MR SOPA (Mask, reposition, suction, open mouth, pressure, airway) (p<0.01), and shortened the time to "positive pressure ventilation" (p<0.01). CONCLUSIONS: In this pilot study, audio-voice guidance application for newborn resuscitation simulation on mannequins, based on the NRP algorithm, improved adherence and performance of NRP guidelines.

Oxygenation Instability Assessed by Oxygen Saturation Histograms during Supine vs Prone Position in Very Low Birthweight Infants Receiving Noninvasive Respiratory Support.

OBJECTIVE: To evaluate the effect of prone vs supine position on the oxygenation instability among very low birth weight (VLBW) infants receiving noninvasive respiratory support, as assessed by the average oxygen saturation (SpO2) histograms. STUDY DESIGN: Sixty-nine histograms from 23 VLBW infants were studied prospectively. Each infant was studied during 3 consecutive 3-hour periods of alternating positions; 12 infants started the study while prone and 11 infants started supine, by random order. Histogram classification system was used to quantify oxygenation stability and time spent in different SpO2 ranges. RESULTS: The fraction of inspired oxygen values were similar in both positions. Unstable histograms were more common in supine vs prone position (20/34 [59%] vs 10/35 [29%]; P = .02, respectively). Analyzing oxygenation stability as per position change revealed that a change from prone to supine increased oxygenation instability, and supine to prone decreased instability (P = .02). In the supine vs prone position, percent of time spent in SpO2 ≤80% and <90% was higher (5.0 ± 4.2 vs 2.4 ± 3.4 [P < .001] and 24.1 ± 13.7 vs 13.2 ± 10.0 [P < .001], respectively), and percent of time in SpO2 >94% was lower (39.7 ± 26.0 vs 52.4 ± 23.4 [P = .04]). CONCLUSIONS: Prone positioning decreased oxygenation instability and resulted in higher oxygenation among VLBW premature infants on noninvasive respiratory support. SpO2 histograms allow easy bedside assessment of oxygenation instability, and quantification of the time spent at different SpO2 ranges.

Clinical quantification of SpO2 instability using a new histogram classification system: a clinical study.

BACKGROUND: Oxygenation instability is not quantified or documented despite being common and correlated with neonatal morbidities, retinopathy of prematurity, and adverse 18-month outcomes. METHODS: We developed a five-type SpO2 histogram classification system based on the SpO2 difference within the 10-90th cumulative time percentile (A) and the time percentage with SpO2 ≤80% (B). In type 1, A is <5% and in type 5, A and B are ≥10%. We then studied consecutive 12-h SpO2 frequency histograms in all infants ≤34 weeks gestation receiving respiratory support on day 1, over 6 months. RESULTS: Six thousand and sixteen histograms were obtained in 73 infants, 28.9 ± 3.0 weeks gestation, and birth weight (BW) 1318.5 ± 495 g. All types were common and did not overlap. Type 3-5 ("unstable") histograms were more common in oxygen or any intubated support. Time in SpO2 <85% and <80% progressively increased in types 3-5. Among histograms in oxygen, the mean (±SD) of SpO2 medians was 92.8 ± 1.9. Infants ≤28 weeks exhibited three phases of SpO2 instability (stable-unstable-stable). Those developing unstable histograms during the first week received longer ventilatory support (median [IQR], 101 [66] vs. 62 [28] days) and supplemental oxygen (62.5 [72] vs. 40.5 [40] days), and more were on ventilatory support at 40 weeks (7/15 vs. 0/10). CONCLUSIONS: Classified SpO2 histograms quantify and document SpO2 instability and identify early infants at risk of prolonged respiratory support, while median SpO2 does not.

Neonatal frontal lobe: sonographic reference values and suggested clinical use.

BACKGROUND: Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHHC) remain major problems among premature infants. The need, timing and type of ventricular drainage are based on sonographic ventricular measures, without assessment of the dimensions of the frontal lobe. The aim of our study was to establish new reference values for sonographic frontal lobe cortico-ventricular thickness (FL-CVT) in a large cohort of infants. METHODS: All normal head ultrasound scans that were performed in our center during the first 4 days of life between January 2014 and December 2016 were retrospectively evaluated. RESULTS: Scans were evaluated and plotted to create a reference range for the thickness of the frontal lobe in normal infants of 24-40 weeks' gestation. The FL-CVT increased significantly during gestation. Calculating the area under the curve of the FL-CVT in 9 infants with post-hemorrhagic-hydrocephalus (PHHC) reveals a 20% mean loss of FL-CVT. The impact of increasing ventricular dilatation and of the various ventricular drainage procedures on the frontal lobe growth were described in two infants demonstrating the potential clinical value of this tool. CONCLUSIONS: Head ultrasound provides a simple, non-invasive method for measuring the thickness of the frontal lobe, which grows significantly between 24 and 40 weeks' gestation. In premature infants with PHHC, we suggest the use of the FL-CVT measure, in addition to ventricular size measures, as a direct assessment of the impact of the enlarged ventricles on the surrounding brain parenchyma. This could assist in the management of PHHC and determine the need and optimal timing for intervention.

[ALTERATIONS IN SENSITIVE MEASURES OF CARDIAC FUNCTION IN HEALTHY NEONATES DURING PHOTOTHERAPY].

OBJECTIVES: Phototherapy has been reported to reduce coronary blood flow in neonates but without affecting gross measures of cardiac function. The aim of our current study was to evaluate earlier, more sensitive changes in cardiac function during phototherapy. METHODS: Nineteen neonates with jaundice treated with phototherapy had Doppler echocardiographic evaluation, before, during and after phototherapy and were compared to 25 matched controls. Sensitive measures for cardiac performance in this study included left ventricular dimension, ventricular Doppler parameters and regional function assessment. RESULTS: Phototherapy was associated with a significant increase in heart rate. In addition, atrioventricular valve closure to opening interval decreased significantly during phototherapy while ventricular ejection times tended to decrease. However, left and right ventricular filling parameters and outflow velocity parameters, longitudinal tissue-Doppler annular velocities and myocardial performance indices were not affected by phototherapy and were similar to those in controls. Coronary blood velocities and integrals decreased significantly during phototherapy. CONCLUSIONS: Our study found no differences in early and sensitive measures of cardiac performance including the diastolic and systolic function, despite modestly lower flow in coronary arteries among healthy neonates during phototherapy.

Ancient Out-of-Africa Mitochondrial DNA Variants Associate with Distinct Mitochondrial Gene Expression Patterns.

Mitochondrial DNA (mtDNA) variants have been traditionally used as markers to trace ancient population migrations. Although experiments relying on model organisms and cytoplasmic hybrids, as well as disease association studies, have served to underline the functionality of certain mtDNA SNPs, only little is known of the regulatory impact of ancient mtDNA variants, especially in terms of gene expression. By analyzing RNA-seq data of 454 lymphoblast cell lines from the 1000 Genomes Project, we found that mtDNA variants defining the most common African genetic background, the L haplogroup, exhibit a distinct overall mtDNA gene expression pattern, which was independent of mtDNA copy numbers. Secondly, intra-population analysis revealed subtle, yet significant, expression differences in four tRNA genes. Strikingly, the more prominent African mtDNA gene expression pattern best correlated with the expression of nuclear DNA-encoded RNA-binding proteins, and with SNPs within the mitochondrial RNA-binding proteins PTCD1 and MRPS7. Our results thus support the concept of an ancient regulatory transition of mtDNA-encoded genes as humans left Africa to populate the rest of the world.

Adding Paracetamol to Ibuprofen for the Treatment of Patent Ductus Arteriosus in Preterm Infants: A Double-Blind, Randomized, Placebo-Controlled Pilot Study.

OBJECTIVE: The objective of this study was to compare the closure rate of hemodynamically significant patent ductus arteriosus (hsPDA) of intravenous ibuprofen + paracetamol (acetaminophen) versus ibuprofen + placebo, in preterm infants of 24 to 316/7 weeks postmenstrual age. STUDY DESIGN: This is a single-center, double-blind, randomized controlled pilot study. Infants were assigned for treatment with either intravenous ibuprofen + paracetamol (n = 12) or ibuprofen + placebo (n = 12). RESULTS: There was no statistical difference in baseline characteristics of the two groups. Echocardiography parameters were comparable before treatment in both groups. There was a trend toward higher hsPDA closure rate in the paracetamol group in comparison to the placebo group (83 vs. 42%, p = 0.08). No adverse effects, clinical or laboratory, were associated with adding paracetamol. CONCLUSION: Our pilot study was unable to detect a beneficial effect by adding intravenous paracetamol to ibuprofen for the treatment of hsPDA. Larger prospective studies are needed to explore the positive tendency suggested by our results and to assure safety.

Narcotics and Sedative Use in Preterm Neonates.

OBJECTIVES: To evaluate patterns of narcotic and sedative use in neonatal intensive care units (NICUs) across Canada using data collected by the Canadian Neonatal Network. STUDY DESIGN: We conducted a retrospective observational cohort study of preterm neonates at <33 weeks' gestation and admitted to a participating Canadian Neonatal Network NICU. The proportion of all neonates who received sedative(s), narcotic(s), or either sedative(s), narcotic(s), or both during their NICU stay was calculated for each year. Because opioids are used for premedication before intubation, only continuous infusions of a narcotic drug were included. Variation in narcotics and sedative usage between sites in 2014 was determined using logistic regression analysis, with adjustment for gestational age, surgery, and mechanical ventilation. RESULTS: Of 20 744 neonates, 29% of neonates received a narcotic, a sedative, or both; 23% received a narcotic and 17% a sedative. Although no clinically significant changes in drug exposure were documented during the 5-year period, there were statistically significant differences in narcotic and sedative use between sites, ranging from 3% to 41% for narcotic and 2% to 48% for sedative use (aORs 0.2-5.7 and 0.1-15, respectively, P < .05). CONCLUSIONS: Exposure to narcotic or sedative agents is highly variable in preterm neonates across Canada despite concerns of adverse outcomes associated with these drugs. The tremendous variation in practice suggests that further research on their current usage, as well as identifying optimal practice procedures is warranted.

[EARLY DETECTION OF ENDOTHELIAL DYSFUNCTION IN CHILDREN WITH AUTOIMMUNE DISEASES BY A NOVEL NONINVASIVE TECHNIQUE].

INTRODUCTION: Atherosclerosis is emerging as one of the most important causes of morbidity and mortality among patients with different rheumatologic disease. Endothelial dysfunction may be an early sign of atherosclerosis. OBJECTIVES: To evaluate the occurrence of endothelial dysfunction in children with autoimmune diseases, including juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE) and dermatomyositis, using a novel noninvasive technique. METHODS: The study group consisted of 24 children with autoimmune diseases, and was compared to a control group of 17 healthy, age- and BMI-matched controls. Endothelial function was assessed by a noninvasive technology that captures a beat-to-beat plethysmographic recording of the finger arterial pulse-wave amplitude with pneumatic probes, utilizing a Peripheral Arterial Tonometry (PAT) device. RESULTS: In the study group, 7 out of the 24 (29%) patients had evidence of impaired endothelial function, compared to 1 out of 17 (6%) children in the control group (p <0.05). Thirty-three per cent of our patients with SLE and 23% of patients with JIA had impaired endothelial function. There were no differences between the two groups of patients with and without endothelial dysfunction as to age, body mass index, fasting glucose level, triglycerides, cholesterol, and dose and duration of steroid treatment. The patients with normal endothelial function had higher systolic blood pressure compared with the group with impaired endothelial function (112.82 ± 7.65 vs13.88 ± 104.85 respectively, p=0.04). CONCLUSIONS: Children with autoimmune diseases may have a high tendency to develop endothelial dysfunction. Larger studies are needed to confirm our findings and to explore the influence of endothelial dysfunction on the development of atherosclerosis in young children.

RNA-DNA differences in human mitochondria restore ancestral form of 16S ribosomal RNA.

RNA transcripts are generally identical to the underlying DNA sequences. Nevertheless, RNA-DNA differences (RDDs) were found in the nuclear human genome and in plants and animals but not in human mitochondria. Here, by deep sequencing of human mitochondrial DNA (mtDNA) and RNA, we identified three RDD sites at mtDNA positions 295 (C-to-U), 13710 (A-to-U, A-to-G), and 2617 (A-to-U, A-to-G). Position 2617, within the 16S rRNA, harbored the most prevalent RDDs (>30% A-to-U and ∼15% A-to-G of the reads in all tested samples). The 2617 RDDs appeared already at the precursor polycistrone mitochondrial transcript. By using traditional Sanger sequencing, we identified the A-to-U RDD in six different cell lines and representative primates (Gorilla gorilla, Pongo pigmaeus, and Macaca mulatta), suggesting conservation of the mechanism generating such RDD. Phylogenetic analysis of more than 1700 vertebrate mtDNA sequences supported a thymine as the primate ancestral allele at position 2617, suggesting that the 2617 RDD recapitulates the ancestral 16S rRNA. Modeling U or G (the RDDs) at position 2617 stabilized the large ribosomal subunit structure in contrast to destabilization by an A (the pre-RDDs). Hence, these mitochondrial RDDs are likely functional.