Therapeutic hypothermia translates from ancient history in to practice

Acute postasphyxial encephalopathy around the time of birth remains a major cause of death and disability. The possibility that hypothermia may be able to prevent or lessen asphyxial brain injury is a “dream revisited”. In this review, a historical perspective is provided from the first reported use of therapeutic hypothermia for brain injuries in antiquity, to the present day. The first uncontrolled trials of cooling for resuscitation were reported more than 50 y ago. The seminal insight that led to the modern revival of studies of neuroprotection was that after profound asphyxia, many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting ~6 h, only to die hours to days later during a “secondary” deterioration phase characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this conceptual framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild induced hypothermia significantly improves intact survival and neurodevelopmental outcomes to midchildhood

Breakdown of the adiabatic limit in low dimensional gapless systems

It is generally believed that a generic system can be reversibly transformed from one state into another by sufficiently slow change of parameters. A standard argument favoring this assertion is based on a possibility to expand the energy or the entropy of the system into the Taylor series in the ramp speed. Here we show that this argumentation is only valid in high enough dimensions and can break down in low-dimensional gapless systems. We identify three generic regimes of a system response to a slow ramp: (A) mean-field, (B) non-analytic, and (C) non-adiabatic. In the last regime the limits of the ramp speed going to zero and the system size going to infinity do not commute and the adiabatic process does not exist in the thermodynamic limit. We support our results by numerical simulations. Our findings can be relevant to condensed-matter, atomic physics, quantum computing, quantum optics, cosmology and others.Comment: 11 pages, 5 figures, to appear in Nature Physics (originally submitted version

Probing Reionization with Quasar Spectra: the Impact of the Intrinsic Lyman-alpha Emission Line Shape Uncertainty

Arguably the best hope of understanding the tail end of the reionization of the intergalactic medium (IGM) at redshift z > 6 is through the detection and characterization of the Gunn-Peterson (GP) damping wing absorption of the IGM in bright quasar spectra. However, the use of quasar spectra to measure the IGM damping wing requires a model of the quasar's intrinsic Lyman-alpha emission line. Here we quantify the uncertainties in the intrinsic line shapes, and how those uncertainties affect the determination of the IGM neutral fraction. We have assembled a catalog of high-resolution HST spectra of the emission lines of unobscured low-redshift quasars, and have characterized the variance in the shapes of their lines. We then add simulated absorption from the high-redshift IGM to these quasar spectra in order to determine the corresponding uncertainties in reionization constraints using current and future samples of z > 6 quasar spectra. We find that, if the redshift of the Lyman-alpha emission line is presumed to coincide with the systemic redshift determined from metal lines, the inferred IGM neutral fraction is systematically biased to low values due to a systematic blueshift of the Lyman-alpha line relative to the metal lines. If a similar blueshift persists in quasars at z > 6, this bias strengthens previous claims of a significant neutral hydrogen fraction at z ~ 6. This technique is capable of making a robust distinction between a highly ionized (x_IGM ~ 10^-3) and a neutral (x_IGM = 1) IGM with even a few bright quasars.Comment: accepted for publication in MNRAS, full tables available at http://www.astro.columbia.edu/~roban

Binary and Millisecond Pulsars at the New Millennium

We review the properties and applications of binary and millisecond pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1300. There are now 56 binary and millisecond pulsars in the Galactic disk and a further 47 in globular clusters. This review is concerned primarily with the results and spin-offs from these surveys which are of particular interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage

RAP80 localizes to sites of DNA insults to enhance the DNA-damage responses. Here we identify TRAIP/RNF206 as a novel RAP80-interacting protein and find that TRAIP is necessary for translocation of RAP80 to DNA lesions. Depletion of TRAIP results in impaired accumulation of RAP80 and functional downstream partners, including BRCA1, at DNA lesions. Conversely, accumulation of TRAIP is normal in RAP80-depleted cells, implying that TRAIP acts upstream of RAP80 recruitment to DNA lesions. TRAIP localizes to sites of DNA damage and cells lacking TRAIP exhibit classical DNA-damage response-defect phenotypes. Biochemical analysis reveals that the N terminus of TRAIP is crucial for RAP80 interaction, while the C terminus of TRAIP is required for TRAIP localization to sites of DNA damage through a direct interaction with RNF20-RNF40. Taken together, our findings demonstrate that the novel RAP80-binding partner TRAIP regulates recruitment of the damage signalling machinery and promotes homologous recombinationopen

The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>A hypoxic-ischaemic insult occurring around the time of birth may result in an encephalopathic state characterised by the need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. There is an increasing risk of death or neurodevelopmental abnormalities with more severe encephalopathy. Current management consists of maintaining physiological parameters within the normal range and treating seizures with anticonvulsants.</p> <p>Studies in adult and newborn animals have shown that a reduction of body temperature of 3–4°C after cerebral insults is associated with improved histological and behavioural outcome. Pilot studies in infants with encephalopathy of head cooling combined with mild whole body hypothermia and of moderate whole body cooling to 33.5°C have been reported. No complications were noted but the group sizes were too small to evaluate benefit.</p> <p>Methods/Design</p> <p>TOBY is a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling".</p> <p>Full-term infants will be randomised within 6 hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2°C or to whole body cooling, with rectal temperature kept at 33–34°C for 72 hours. Term infants showing signs of moderate or severe encephalopathy +/- seizures have their eligibility confirmed by cerebral function monitoring. Outcomes will be assessed at 18 months of age using neurological and neurodevelopmental testing methods.</p> <p>Sample size</p> <p>At least 236 infants would be needed to demonstrate a 30% reduction in the relative risk of mortality or serious disability at 18 months.</p> <p>Recruitment was ahead of target by seven months and approvals were obtained allowing recruitment to continue to the end of the planned recruitment phase. 325 infants were recruited.</p> <p>Primary outcome</p> <p>Combined rate of mortality and severe neurodevelopmental impairment in survivors at 18 months of age. Neurodevelopmental impairment will be defined as any of:</p> <p>• Bayley mental developmental scale score less than 70</p> <p>• Gross Motor Function Classification System Levels III – V</p> <p>• Bilateral cortical visual impairments</p> <p>Trial Registration</p> <p>Current Controlled Trials ISRCTN89547571</p

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Associations between social isolation, pro-social behaviour and emotional development in preschool aged children:a population based survey of kindergarten staff

Peer reviewedPublisher PD

Employment of ex-prisoners with mental health problems, a realistic evaluation protocol

Background Offenders with a mental illness are routinely excluded from vocational services due to their mental health. Employment has shown to be very important in improving mental health, reducing recidivism, and connecting people to society. This study examines the effectiveness of an established intervention which is relatively untested in this population, Individual Placement and Support (IPS), to help offenders with mental health problems into competitive employment. The overall research question is whether IPS is effective in gaining and sustaining competitive employment for offenders with a Severe Mental Illness (SMI). The context is an English criminal justice setting across different populations. The study will also measure non-vocational outcomes such as recidivism, mental health and social stability. Methods/Design A Realistic Evaluation (RE) design will address the questions “What works, for whom, and in what circumstances?” This study includes pre and post comparisons for a cohort of approximately 20 people taking part in IPS, and a similar number of controls, over a one year period. The RE also consists of interviews with practitioners and offenders in order to understand how IPS works and develops within the criminal justice system (CJS). By applying this framework the research can go from discovering whether IPS works, to how and why (or why not) IPS works. This is achieved by examining where the intervention is occurring (Context (C)), the mechanisms (M) that create particular behaviours, and how the outcomes (O) from the intervention all come together (CMOs). Employment outcomes will also be examined for all participants. Discussion By applying RE the research will permit inferences to be drawn about how and why (or why not) IPS works, by examining context, mechanisms and outcomes. IPS has never been implemented within the CJS in the United Kingdom. As a result, this evaluative research will not only provide a novel insight into the core research areas, but also how the intervention can be improved for others in the future