Rapamycin - "One size does not fit all"

Non peer reviewe

Statistical language learning in neonates revealed by event-related brain potentials

<p>Abstract</p> <p>Background</p> <p>Statistical learning is a candidate for one of the basic prerequisites underlying the expeditious acquisition of spoken language. Infants from 8 months of age exhibit this form of learning to segment fluent speech into distinct words. To test the statistical learning skills at birth, we recorded event-related brain responses of sleeping neonates while they were listening to a stream of syllables containing statistical cues to word boundaries.</p> <p>Results</p> <p>We found evidence that sleeping neonates are able to automatically extract statistical properties of the speech input and thus detect the word boundaries in a continuous stream of syllables containing no morphological cues. Syllable-specific event-related brain responses found in two separate studies demonstrated that the neonatal brain treated the syllables differently according to their position within pseudowords.</p> <p>Conclusion</p> <p>These results demonstrate that neonates can efficiently learn transitional probabilities or frequencies of co-occurrence between different syllables, enabling them to detect word boundaries and in this way isolate single words out of fluent natural speech. The ability to adopt statistical structures from speech may play a fundamental role as one of the earliest prerequisites of language acquisition.</p

COX7A2L/SCAFI and Pre-Complex III Modify Respiratory Chain Supercomplex Formation in Different Mouse Strains with a Bcs1/Mutation

The COX7A2L (Supercomplex Assembly Factor I, SCAFI) protein has been proposed to be a mitochondrial supercomplex assembly factor required for respirasome (supercomplex containing complexes I, III, and IV) formation. In the C57BU6 mouse strain a homozygous in-frame 6-base-pair deletion in the COX7a2I/SCAF1 gene resulting in unstable protein and suggesting loss of function was previously identified. The loss of SCAFI was shown to impede respirasome formation, a major concern for the use of C57BL mouse strains in mitochondrial research. In contradiction, another recent study suggested that supercomplex formation is independent of SCAFI isoforms. We investigated whether SCAFI isoform status affected the disease severity and supercomplex formation in the liver of Bcs1a232A>G knock-in mice with incomplete complex III assembly. In homozygotes (Bcs1/(G/G)) of mixed (C57BL/6:129/Sv) genetic background, the lifespan was similar in mice with wild-type SCAFI allele and in those homozygous (SCAF/(short/short)) for the deleted SCAF1 variant (34 3 days; n = 6 vs. 32 +/- 2 days; n = 7, respectively). SCAFI heterozygosity (SCAF/(long/short)) resulted in decreased SCAFI protein but respirasome assembly was unaffected. Congenic (C57BL/6) mice were of the genotype SCAF(short/short) and had no detectable SCAFI protein. In their liver mitochondria, respirasome composition was altered as compared to mixed background mice. Complex IV was mainly present as monomers and dimers, and only low amounts were found in combination with complex I and complex III or with precomplex III. The main supercomplex in the liver mitochondria of C57BU6 mice comprised only complexes I and III. In conclusion, in liver mitochondria of C57BL/6 mice, supercomplexes had markedly reduced amount of, but were not completely depleted of, complex IV, supporting a role for COX7A2L/SCAFI in supercomplex assembly. However, the disease progression of the Bcs1/mutant mice was unrelated to SCAFI isoforms and supercomplex composition, suggesting that other genetic factors contribute to the different survival in the different genetic backgrounds.Peer reviewe

Newborn infants' auditory system is sensitive to Western music chord categories

Neural encoding of abstract rules in the audition of newborn infants has been recently demonstrated in several studies using event-related potentials (ERPs). In the present study the neural encoding of Western music chords was investigated in newborn infants. Using ERPs, we examined whether the categorizations of major vs. minor and consonance vs. dissonance are present at the level of the change-related mismatch response (MMR). Using an oddball paradigm, root minor, dissonant and inverted major chords were presented in a context of consonant root major chords. The chords were transposed to several different frequency levels, so that the deviant chords did not include a physically deviant frequency that could result in an MMR without categorization. The results show that the newborn infants were sensitive to both dissonant and minor chords but not to inverted major chords in the context of consonant root major chords. While the dissonant chords elicited a large positive MMR, the minor chords elicited a negative MMR. This indicates that the two categories were processed differently. The results suggest newborn infants are sensitive to Western music categorizations, which is consistent with the authors' previous studies in adults and school-aged children.Peer reviewe

Premedication for intubation with morphine causes prolonged depression of electrocortical background activity in preterm infants.

Background:Sedative and analgesic medications are used in critically ill newborns, but little is known about their effects on electrocortical activity in preterm infants. We hypothesized that morphine might induce prolonged neurodepression, independent of blood pressure, compared with rapid sequence induction/intubation (RSI).Methods:Of 34 infants enrolled into a randomized controlled trial (RCT) comparing RSI (including thiopental 2-3 mg/kg and remifentantil 1 microg/kg) with morphine (0.3 mg/kg) as premedication for intubation, 28 infants (n=14+14; median gestational age 26.1 weeks and postnatal age 138 h) had continuous two-channel amplitude-integrated electroencephalogram (aEEG/EEG) and blood pressure monitoring during 24 h after the intubation. Thirteen infants not receiving any additional medication constituted the primary study group. Visual and quantitative analyses of aEEG/EEG and blood pressure were performed in 3-h epochs.Results:RSI was associated with aEEG/EEG depression lasting less than 3 h. Morphine premedication resulted in aEEG/EEG depression with more discontinuous background and less developed cyclicity for 24 h, and during the first 9 h interburst intervals were significantly increased compared to RSI. The difference was not related to blood pressure.Conclusion:Premedication with morphine is associated with prolonged aEEG/EEG depression independent of blood pressure changes, and may not be optimal for short procedures.Pediatric Research (2012); doi:10.1038/pr.2012.153

A sensitive assay for dNTPs based on long synthetic oligonucleotides, EvaGreen dye and inhibitor-resistant high-fidelity DNA polymerase

Deoxyribonucleoside triphosphates (dNTPs) are vital for the biosynthesis and repair of DNA. Their cellular concentration peaks during the S phase of the cell cycle. In non-proliferating cells, dNTP concentrations are low, making their reliable quantification from tissue samples of heterogeneous cellular composition challenging. Partly because of this, the current knowledge related to the regulation of and disturbances in cellular dNTP concentrations derive mostly from cell culture experiments with little corroboration at the tissue or organismal level. Here, we fill the methodological gap by presenting a simple non-radioactive microplate assay for the quantification of dNTPs with a minimum requirement of 4-12 mg of biopsy material. In contrast to published assays, this assay is based on long synthetic single-stranded DNA templates (50-200 nucleotides), an inhibitor-resistant high-fidelity DNA polymerase, and the double-stranded-DNA-binding EvaGreen dye. The assay quantified reliably less than 50 fmol of each of the four dNTPs and discriminated well against ribonucleotides. Additionally, thermostable RNAse HII-mediated nicking of the reaction products and a subsequent shift in their melting temperature allowed near-complete elimination of the interfering ribonucleotide signal, if present. Importantly, the assay allowed measurement of minute dNTP concentrations in mouse liver, heart and skeletal muscle.Peer reviewe

Auditory Processing of the Brain Is Enhanced by Parental Singing for Preterm Infants

As the human auditory system is highly malleable in infancy, perinatal risk factors, such as preterm birth, may affect auditory development. In comparison to healthy full-term infants, preterm infants show abnormal auditory brain responses at term age, which may have long-term detrimental outcomes. To achieve an optimal neonatal care environment for preterm-born infants, many early interventions have been developed. Musical interventions developed for neonatal intensive care units (NICUs) have shown beneficial effects on vital functions and weight gain of preterm infants and might also influence basic auditory processing and thereby enhance outcomes. In the present study, we tested the effect of parental singing during kangaroo care on auditory processing of standardized audio stimuli. Preterm infants (born between 24 and 32 weeks of gestation) were randomized to singing intervention (n = 13) or control (n = 8) groups. The auditory processing was tested using two audio paradigms assessed with magnetoencephalography (MEG) at term corresponding age. To verify that the paradigms elicit responses in MEG, we studied 12 healthy full-term infants. In the singing intervention group, parents were instructed by a music therapist twice a week for 4 weeks to sing or hum during kangaroo care in an infant-directed way. The control group received standard kangaroo care. The results show that the infants in the singing intervention group show larger neural responses than those in the control group when controlling for the total amount of singing during kangaroo care. Our findings suggest that incorporating singing into kangaroo care may be beneficial for preterm infants, but the effect may not be due to exposure to singing but instead positive parenting, improved parental self-esteem and improved caregiver sensitivity.Peer reviewe

Auditory event-related potentials at preschool age in children born very preterm.

To assess auditory event-related potentials at preschool age in children born very preterm (VP, 27.4±1.9 gestational weeks, n=70) with a high risk of cognitive dysfunction

Rapid Sequence Induction is Superior to Morphine for Intubation of Preterm Infants: A Randomized Controlled Trial.

OBJECTIVES: To compare rapid sequence intubation (RSI) premedication with morphine for intubation of preterm infants. STUDY DESIGN: Preterm infants needing semi-urgent intubation were enrolled to either RSI (glycopyrrolate, thiopental, suxamethonium, and remifentanil, n = 17) or atropine and morphine (n = 17) in a randomized trial. The main outcome was "good intubation conditions" (score ≤10 assessed with intubation scoring), and secondary outcomes were procedural duration, physiological and biochemical variables, amplitude-integrated electroencephalogram, and pain scores. RESULTS: Infants receiving RSI had superior intubation conditions (16/17 versus 1/17, P < .001), the median (IQR) intubation score was 5 (5-6) compared with 12 (10.0-13.5, P < .001), and a shorter procedure duration of 45 seconds (35-154) compared with 97 seconds (49-365, P = .031). The morphine group had prolonged heart rate decrease (area under the curve, P < .009) and mean arterial blood pressure increase (area under the curve, P < .005 and %change: mean ± SD 21% ± 23% versus -2% ± 22%, P < .007) during the intubation, and a subsequent lower mean arterial blood pressure 3 hours after the intubation compared with baseline (P = .033), concomitant with neurophysiologic depression (P < .001) for 6 hours after. Plasma cortisol and stress/pain scores were similar. CONCLUSION: RSI with the drugs used can be implemented as medication for semi-urgent intubation in preterm infants. Because of circulatory changes and neurophysiological depression found during and after the intubation in infants given morphine, premedication with morphine should be avoided

Complex I Function and Supercomplex Formation Are Preserved in Liver Mitochondria Despite Progressive Complex III Deficiency

Peer reviewe