Hypothermia for perinatal asphyxial encephalopathy. A Swiss survey of opinion, practice and cerebral investigations

BACKGROUND: Perinatal asphyxial encephalopathy occurs in 1-per 1000 live births and is associated with high mortality and morbidity. Therapeutic hypothermia increases intact survival and improves neurodevelopmental outcome in survivors.AIMS: To evaluate (i) the opinion and practice of therapeutic hypothermia as a therapy for moderate to severe perinatal asphyxial encephalopathy amongst Swiss neonatologists and paediatric intensive care specialists, (ii) the current clinical management of infants with perinatal asphyxial encephalopathy and (iii) the need for a national perinatal asphyxia and therapeutic hypothermia registry.METHODS: Two web-based questionnaires were sent to 18 senior staff physicians within the Swiss Neonatal Network.RESULTS: Therapeutic hypothermia was considered effective by all responders, however only 11 of 18 units provided therapeutic hypothermia. Cooling was initiated during transfer and performed passively in 82% of centres with a target rectal temperature of 33-34 degrees C. Most units ventilated infants with perinatal asphyxial encephalopathy if clinically indicated and 73% of responders gave analgesia routinely to cooled infants. Neuromonitoring included continuous amplitude integrated EEG (aEEG) and EEG. Neuroimaging included cranial ultrasound (cUS), magnetic resonance imaging (MRI) and computed tomography (CT). Sixty-seven percent of units treating infants with perinatal asphyxial encephalopathy performed MRI routinely. All heads of departments questioned indicated that a "Swiss National Asphyxia and Cooling Registry" is needed.CONCLUSIONS: In Switzerland, access to therapeutic hypothermia is widespread and Swiss neonatologists believe that therapeutic hypothermia for perinatal asphyxia is effective. National cooling protocols are needed for the management of infants with perinatal asphyxial encephalopathy in order to ensure safe cooling, appropriate monitoring, imaging and follow-up assessment. A national registry is needed to collect data on diagnosis, treatment, adverse events and outcome

Transport theory yields renormalization group equations

We show that dissipative transport and renormalization can be described in a single theoretical framework. The appropriate mathematical tool is the Nakajima-Zwanzig projection technique. We illustrate our result in the case of interacting quantum gases, where we use the Nakajima-Zwanzig approach to investigate the renormalization group flow of the effective two-body interaction.Comment: 11 pages REVTeX, twocolumn, no figures; revised version with additional examples, to appear in Phys. Rev.

Early cranial ultrasound findings among infants with neonatal encephalopathy in Uganda: an observational study.

BACKGROUND: In sub-Saharan Africa, the timing and nature of brain injury and their relation to mortality in neonatal encephalopathy (NE) are unknown. We evaluated cranial ultrasound (cUS) scans from term Ugandan infants with and without NE for evidence of brain injury. METHODS: Infants were recruited from a national referral hospital in Kampala. Cases (184) had NE and controls (100) were systematically selected unaffected term infants. All had cUS scans <36 h reported blind to NE status. RESULTS: Scans were performed at median age 11.5 (interquartile range (IQR): 5.2-20.2) and 8.4 (IQR: 3.6-13.5) hours, in cases and controls respectively. None had established antepartum injury. Major evolving injury was reported in 21.2% of the cases vs. 1.0% controls (P < 0.001). White matter injury was not significantly associated with bacteremia in encephalopathic infants (odds ratios (OR): 3.06 (95% confidence interval (CI): 0.98-9.60). Major cUS abnormality significantly increased the risk of neonatal death (case fatality 53.9% with brain injury vs. 25.9% without; OR: 3.34 (95% CI: 1.61-6.95)). CONCLUSION: In this low-resource setting, there was no evidence of established antepartum insult, but a high proportion of encephalopathic infants had evidence of major recent and evolving brain injury on early cUS imaging, suggesting prolonged or severe acute exposure to hypoxia-ischemia (HI). Early abnormalities were a significant predictor of death

RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus

Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active. Consistent with pol II stalling, we detect considerable pausing complex (NELF/DSIF) association with Cp. Significantly, we observe substantial Cp-specific pTEFb recruitment that stimulates high-level pol II CTD serine 2 phosphorylation at distal regions (up to +75 kb), promoting elongation. We reveal that Cp-specific pol II accumulation is directed by DNA sequences unfavourable for nucleosome assembly that increase TBP access and pol II recruitment. Stalled pol II then maintains Cp nucleosome depletion. Our data indicate that pTEFb is recruited to Cp by the bromodomain protein Brd4, with polymerase stalling facilitating stable association of pTEFb. The Brd4 inhibitor JQ1 and the pTEFb inhibitors DRB and Flavopiridol significantly reduce Cp, but not LMP1 transcript production indicating that Brd4 and pTEFb are required for Cp transcription. Taken together our data indicate that pol II stalling at Cp promotes transcription of essential immortalizing genes during EBV infection by (i) preventing promoter-proximal nucleosome assembly and ii) necessitating the recruitment of pTEFb thereby maintaining serine 2 CTD phosphorylation at distal regions

Impact of facial conformation on canine health: Brachycephalic Obstructive Airway Syndrome

The domestic dog may be the most morphologically diverse terrestrial mammalian species known to man; pedigree dogs are artificially selected for extreme aesthetics dictated by formal Breed Standards, and breed-related disorders linked to conformation are ubiquitous and diverse. Brachycephaly–foreshortening of the facial skeleton–is a discrete mutation that has been selected for in many popular dog breeds e.g. the Bulldog, Pug, and French Bulldog. A chronic, debilitating respiratory syndrome, whereby soft tissue blocks the airways, predominantly affects dogs with this conformation, and thus is labelled Brachycephalic Obstructive Airway Syndrome (BOAS). Despite the name of the syndrome, scientific evidence quantitatively linking brachycephaly with BOAS is lacking, but it could aid efforts to select for healthier conformations. Here we show, in (1) an exploratory study of 700 dogs of diverse breeds and conformations, and (2) a confirmatory study of 154 brachycephalic dogs, that BOAS risk increases sharply in a non-linear manner as relative muzzle length shortens. BOAS only occurred in dogs whose muzzles comprised less than half their cranial lengths. Thicker neck girths also increased BOAS risk in both populations: a risk factor for human sleep apnoea and not previously realised in dogs; and obesity was found to further increase BOAS risk. This study provides evidence that breeding for brachycephaly leads to an increased risk of BOAS in dogs, with risk increasing as the morphology becomes more exaggerated. As such, dog breeders and buyers should be aware of this risk when selecting dogs, and breeding organisations should actively discourage exaggeration of this high-risk conformation in breed standards and the show ring

Beyond the required LISA free-fall performance: new LISA pathfinder results down to 20 μHz

In the months since the publication of the first results, the noise performance of LISA Pathfinder has improved because of reduced Brownian noise due to the continued decrease in pressure around the test masses, from a better correction of noninertial effects, and from a better calibration of the electrostatic force actuation. In addition, the availability of numerous long noise measurement runs, during which no perturbation is purposely applied to the test masses, has allowed the measurement of noise with good statistics down to 20  μHz. The Letter presents the measured differential acceleration noise figure, which is at (1.74±0.05)  fm s^{-2}/sqrt[Hz] above 2 mHz and (6±1)×10  fm s^{-2}/sqrt[Hz] at 20  μHz, and discusses the physical sources for the measured noise. This performance provides an experimental benchmark demonstrating the ability to realize the low-frequency science potential of the LISA mission, recently selected by the European Space Agency

Turbulence and galactic structure

Interstellar turbulence is driven over a wide range of scales by processes including spiral arm instabilities and supernovae, and it affects the rate and morphology of star formation, energy dissipation, and angular momentum transfer in galaxy disks. Star formation is initiated on large scales by gravitational instabilities which control the overall rate through the long dynamical time corresponding to the average ISM density. Stars form at much higher densities than average, however, and at much faster rates locally, so the slow average rate arises because the fraction of the gas mass that forms stars at any one time is low, ~10^{-4}. This low fraction is determined by turbulence compression, and is apparently independent of specific cloud formation processes which all operate at lower densities. Turbulence compression also accounts for the formation of most stars in clusters, along with the cluster mass spectrum, and it gives a hierarchical distribution to the positions of these clusters and to star-forming regions in general. Turbulent motions appear to be very fast in irregular galaxies at high redshift, possibly having speeds equal to several tenths of the rotation speed in view of the morphology of chain galaxies and their face-on counterparts. The origin of this turbulence is not evident, but some of it could come from accretion onto the disk. Such high turbulence could help drive an early epoch of gas inflow through viscous torques in galaxies where spiral arms and bars are weak. Such evolution may lead to bulge or bar formation, or to bar re-formation if a previous bar dissolved. We show evidence that the bar fraction is about constant with redshift out to z~1, and model the formation and destruction rates of bars required to achieve this constancy.Comment: in: Penetrating Bars through Masks of Cosmic Dust: The Hubble Tuning Fork strikes a New Note, Eds., K. Freeman, D. Block, I. Puerari, R. Groess, Dordrecht: Kluwer, in press (presented at a conference in South Africa, June 7-12, 2004). 19 pgs, 5 figure

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Risk-taking behaviour of Cape Peninsula high school students

Objectives. To ascertain whether the notion of a syndrome of adolescent risk behaviour (which includes problem drinking, marijuana use, having experienced sexual intercourse, 'general deviance' and cigarette smoking) is valid for this setting; and to investigate whether suicidal behaviour and behaviour that exposes the adolescent to injury should be included in this syndrome. Design. Cross-sectional survey utilising a self-completed questionnaire; for both sexes, relationships between behaviours were documented as odds ratios. Setting. High schools in the Cape Peninsula, South Africa. Subjects. 7 340 students from 16 schools in the three major ed ucation departments. Outcome measures. Participation in the following behaviours: alcohol bingeing, cannabis smoking, sexual intercourse, knife-carrying at school, cigarette smoking, attempting suicide, failure to use a seat belt, and walking home at night from beyond the neighbourhood. Results. All the odds ratios were greater than 1. There were statisticaHy significant odds ratios between all the pairs of risk behaviours included in the 'original' syndrome of risk behaviour except for cigarette smoking and having had sexual intercourse in the case of girls. There were statistically significant relationships between all these risk behaviours, suicidal behaviour, and behaviours that exposed the adolescent to risk of physical injury, except for failure to use a seat belt and: (I) suicidal behaviour for both sexes; and (iI) walking home alone at night and having had sexual intercourse in the case of gins. Conclusion. The notion of a syndrome of adolescent risk behaviour is valid for this population, and both suicidal behaviour and behaviour that exposes the adolescent to injury should be included in this syndrome.S Afr Med J 1996; 86; 1090-1093