A noninvasive estimation of cerebral perfusion pressure using critical closing pressure.

OBJECT: Cerebral blood flow is associated with cerebral perfusion pressure (CPP), which is clinically monitored through arterial blood pressure (ABP) and invasive measurements of intracranial pressure (ICP). Based on critical closing pressure (CrCP), the authors introduce a novel method for a noninvasive estimator of CPP (eCPP). METHODS: Data from 280 head-injured patients with ABP, ICP, and transcranial Doppler ultrasonography measurements were retrospectively examined. CrCP was calculated with a noninvasive version of the cerebrovascular impedance method. The eCPP was refined with a predictive regression model of CrCP-based estimation of ICP from known ICP using data from 232 patients, and validated with data from the remaining 48 patients. RESULTS: Cohort analysis showed eCPP to be correlated with measured CPP (R = 0.851, p < 0.001), with a mean ± SD difference of 4.02 ± 6.01 mm Hg, and 83.3% of the cases with an estimation error below 10 mm Hg. eCPP accurately predicted low CPP (< 70 mm Hg) with an area under the curve of 0.913 (95% CI 0.883-0.944). When each recording session of a patient was assessed individually, eCPP could predict CPP with a 95% CI of the SD for estimating CPP between multiple recording sessions of 1.89-5.01 mm Hg. CONCLUSIONS: Overall, CrCP-based eCPP was strongly correlated with invasive CPP, with sensitivity and specificity for detection of low CPP that show promise for clinical use.G. Varsos is supported by an A. G. Leventis Foundation Scholarship and a Charter Studentship from St. Edmund’s College, Cambridge. Dr. Kolias is supported by a Royal College of Surgeons of England Research Fellowship, a National Institute for Health Research (NIHR) Academic Clinical Fellowship, and a Raymond and Beverly Sackler Studentship. He also chairs the British Neurosurgical Trainee Research Collaborative, which has been supported with an educational grant from Codman. Dr. Hutchinson is supported by an NIHR Research Professorship, the NIHR Cambridge Biomedical Research Centre, and has been appointed as the Surgical Specialty Lead for Neurosurgery, Royal College of Surgeons of England Clinical Research Initiative. He is a director of Technicam, a manufacturer of cranial access devices for neuromonitoring. He has also received honoraria from Codman. J. Pickard’s research (excluding salary) is supported by the NIHR Cambridge Biomedical Research Centre and an NIHR Senior Investigator Award. ICM+ Software is licensed by Cambridge Enterprise, Cambridge, UK, and Dr. Czosnyka and Dr. Smielewski have a financial interest in a fraction of the licensing fee. Dr. Czosnyka has also served as a consultant to Codman.This is the author accepted manuscript. The final version is available from American Association of Neurological Surgeons via http://dx.doi.org/10.3171/2014.10.JNS14613

Comparison of frequency and time domain methods of assessment of cerebral autoregulation in traumatic brain injury.

The impulse response (IR)-based autoregulation index (ARI) allows for continuous monitoring of cerebral autoregulation using spontaneous fluctuations of arterial blood pressure (ABP) and cerebral flow velocity (FV). We compared three methods of autoregulation assessment in 288 traumatic brain injury (TBI) patients managed in the Neurocritical Care Unit: (1) IR-based ARI; (2) transfer function (TF) phase, gain, and coherence; and (3) mean flow index (Mx). Autoregulation index was calculated using the TF estimation (Welch method) and classified according to the original Tiecks' model. Mx was calculated as a correlation coefficient between 10-second averages of ABP and FV using a moving 300-second data window. Transfer function phase, gain, and coherence were extracted in the very low frequency (VLF, 0 to 0.05 Hz) and low frequency (LF, 0.05 to 0.15 Hz) bandwidths. We studied the relationship between these parameters and also compared them with patients' Glasgow outcome score. The calculations were performed using both cerebral perfusion pressure (CPP; suffix 'c') as input and ABP (suffix 'a'). The result showed a significant relationship between ARI and Mx when using either ABP (r=-0.38, P<0.001) or CPP (r=-0.404, P<0.001) as input. Transfer function phase and coherence_a were significantly correlated with ARI_a and ARI_c (P<0.05). Only ARI_a, ARI_c, Mx_a, Mx_c, and phase_c were significantly correlated with patients' outcome, with Mx_c showing the strongest association.This is the accepted manuscript. The final version's available from Nature Publishing at http://dx.doi/10.1038/jcbfm.2014.192

Comparison of wavelet and correlation indices of cerebral autoregulation in a pediatric swine model of cardiac arrest

Abstract: Existing cerebrovascular blood pressure autoregulation metrics have not been translated to clinical care for pediatric cardiac arrest, in part because signal noise causes high index time-variability. We tested whether a wavelet method that uses near-infrared spectroscopy (NIRS) or intracranial pressure (ICP) decreases index variability compared to that of commonly used correlation indices. We also compared whether the methods identify the optimal arterial blood pressure (ABPopt) and lower limit of autoregulation (LLA). 68 piglets were randomized to cardiac arrest or sham procedure with continuous monitoring of cerebral blood flow using laser Doppler, NIRS and ICP. The arterial blood pressure (ABP) was gradually reduced until it dropped to below the LLA. Several autoregulation indices were calculated using correlation and wavelet methods, including the pressure reactivity index (PRx and wPRx), cerebral oximetry index (COx and wCOx), and hemoglobin volume index (HVx and wHVx). Wavelet methodology had less index variability with smaller standard deviations. Both wavelet and correlation methods distinguished functional autoregulation (ABP above LLA) from dysfunctional autoregulation (ABP below the LLA). Both wavelet and correlation methods also identified ABPopt with high agreement. Thus, wavelet methodology using NIRS may offer an accurate vasoreactivity monitoring method with reduced signal noise after pediatric cardiac arrest

Comparison of wavelet and correlation indices of cerebral autoregulation in a pediatric swine model of cardiac arrest

Abstract: Existing cerebrovascular blood pressure autoregulation metrics have not been translated to clinical care for pediatric cardiac arrest, in part because signal noise causes high index time-variability. We tested whether a wavelet method that uses near-infrared spectroscopy (NIRS) or intracranial pressure (ICP) decreases index variability compared to that of commonly used correlation indices. We also compared whether the methods identify the optimal arterial blood pressure (ABPopt) and lower limit of autoregulation (LLA). 68 piglets were randomized to cardiac arrest or sham procedure with continuous monitoring of cerebral blood flow using laser Doppler, NIRS and ICP. The arterial blood pressure (ABP) was gradually reduced until it dropped to below the LLA. Several autoregulation indices were calculated using correlation and wavelet methods, including the pressure reactivity index (PRx and wPRx), cerebral oximetry index (COx and wCOx), and hemoglobin volume index (HVx and wHVx). Wavelet methodology had less index variability with smaller standard deviations. Both wavelet and correlation methods distinguished functional autoregulation (ABP above LLA) from dysfunctional autoregulation (ABP below the LLA). Both wavelet and correlation methods also identified ABPopt with high agreement. Thus, wavelet methodology using NIRS may offer an accurate vasoreactivity monitoring method with reduced signal noise after pediatric cardiac arrest

Elevated Diastolic Closing Margin Is Associated with Intraventricular Hemorrhage in Premature Infants.

OBJECTIVE: To determine whether the diastolic closing margin (DCM), defined as diastolic blood pressure minus critical closing pressure, is associated with the development of early severe intraventricular hemorrhage (IVH). STUDY DESIGN: A reanalysis of prospectively collected data was conducted. Premature infants (gestational age 23-31 weeks) receiving mechanical ventilation (n = 185) had ∼1-hour continuous recordings of umbilical arterial blood pressure, middle cerebral artery cerebral blood flow velocity, and PaCO2 during the first week of life. Models using multivariate generalized linear regression and purposeful selection were used to determine associations with severe IVH. RESULTS: Severe IVH (grades 3-4) was observed in 14.6% of the infants. Irrespective of the model used, Apgar score at 5 minutes and DCM were significantly associated with severe IVH. A clinically relevant 5-mm Hg increase in DCM was associated with a 1.83- to 1.89-fold increased odds of developing severe IVH. CONCLUSION: Elevated DCM was associated with severe IVH, consistent with previous animal data showing that IVH is associated with hyperperfusion. Measurement of DCM may be more useful than blood pressure in defining cerebral perfusion in premature infants.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Oxford University Press

Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells

Interferon-producing killer dendritic cells (IKDCs) have been described as possessing the lytic potential of NK cells and the antigen-presenting capacity of dendritic cells (DCs). In this study, we examine the lytic function and antigen-presenting capacity of mouse spleen IKDCs, including those found in DC preparations. IKDCs efficiently killed NK cell targets, without requiring additional activation stimuli. However, in our hands, when exposed to protein antigen or to MHC class II peptide, IKDCs induced little or no T cell proliferation relative to conventional DCs or plasmacytoid DCs, either before or after activation with CpG, or in several disease models. Certain developmental features indicated that IKDCs resembled NK cells more than DCs. IKDCs, like NK cells, did not express the transcription factor PU.1 and were absent from recombinase activating gene-2–null, common γ-chain–null (Rag2−/−Il2rg−/−) mice. When cultured with IL-15 and -18, IKDCs proliferated extensively, like NK cells. Under these conditions, a proportion of expanded IKDCs and NK cells expressed high levels of surface MHC class II. However, even such MHC class II+ IKDCs and NK cells induced poor T cell proliferative responses compared with DCs. Thus, IKDCs resemble NK cells functionally, and neither cell type could be induced to be effective antigen-presenting cells

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Neonatal cerebrovascular autoregulation.

Cerebrovascular pressure autoregulation is the physiologic mechanism that holds cerebral blood flow (CBF) relatively constant across changes in cerebral perfusion pressure (CPP). Cerebral vasoreactivity refers to the vasoconstriction and vasodilation that occur during fluctuations in arterial blood pressure (ABP) to maintain autoregulation. These are vital protective mechanisms of the brain. Impairments in pressure autoregulation increase the risk of brain injury and persistent neurologic disability. Autoregulation may be impaired during various neonatal disease states including prematurity, hypoxic-ischemic encephalopathy (HIE), intraventricular hemorrhage, congenital cardiac disease, and infants requiring extracorporeal membrane oxygenation (ECMO). Because infants are exquisitely sensitive to changes in cerebral blood flow (CBF), both hypoperfusion and hyperperfusion can cause significant neurologic injury. We will review neonatal pressure autoregulation and autoregulation monitoring techniques with a focus on brain protection. Current clinical therapies have failed to fully prevent permanent brain injuries in neonates. Adjuvant treatments that support and optimize autoregulation may improve neurologic outcomes

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae

We systematically surveyed period variations of superhumps in SU UMa-type dwarf novae based on newly obtained data and past publications. In many systems, the evolution of superhump period are found to be composed of three distinct stages: early evolutionary stage with a longer superhump period, middle stage with systematically varying periods, final stage with a shorter, stable superhump period. During the middle stage, many systems with superhump periods less than 0.08 d show positive period derivatives. Contrary to the earlier claim, we found no clear evidence for variation of period derivatives between superoutburst of the same object. We present an interpretation that the lengthening of the superhump period is a result of outward propagation of the eccentricity wave and is limited by the radius near the tidal truncation. We interpret that late stage superhumps are rejuvenized excitation of 3:1 resonance when the superhumps in the outer disk is effectively quenched. Many of WZ Sge-type dwarf novae showed long-enduring superhumps during the post-superoutburst stage having periods longer than those during the main superoutburst. The period derivatives in WZ Sge-type dwarf novae are found to be strongly correlated with the fractional superhump excess, or consequently, mass ratio. WZ Sge-type dwarf novae with a long-lasting rebrightening or with multiple rebrightenings tend to have smaller period derivatives and are excellent candidate for the systems around or after the period minimum of evolution of cataclysmic variables (abridged).Comment: 239 pages, 225 figures, PASJ accepte

Minichromosome Maintenance 2 Bound with Retroviral Gp70 Is Localized to Cytoplasm and Enhances DNA-Damage-Induced Apoptosis

The interaction of viral proteins with host-cellular proteins elicits the activation of cellular signal transduction pathways and possibly leads to viral pathogenesis as well as cellular biological events. Apoptotic signals induced by DNA-damage are remarkably up-regulated by Friend leukemia virus (FLV) exclusively in C3H hosts; however, the mechanisms underlying the apoptosis enhancement and host-specificity are unknown. Here, we show that C3H mouse-derived hematopoietic cells originally express higher levels of the minichromosome maintenance (MCM) 2 protein than BALB/c- or C57BL/6-deriverd cells, and undergo more frequent apoptosis following doxorubicin-induced DNA-damage in the presence of the FLV envelope protein gp70. Dual transfection with gp70/Mcm2 reproduced doxorubicin-induced apoptosis even in BALB/c-derived 3T3 cells. Immunoprecipitation assays using various deletion mutants of MCM2 revealed that gp70 bound to the nuclear localization signal (NLS) 1 (amino acids 18–24) of MCM2, interfered with the function of NLS2 (amino acids 132–152), and suppressed the normal nuclear-import of MCM2. Cytoplasmic MCM2 reduced the activity of protein phosphatase 2A (PP2A) leading to the subsequent hyperphosphorylation of DNA-dependent protein kinase (DNA-PK). Phosphorylated DNA-PK exhibited elevated kinase activity to phosphorylate P53, thereby up-regulating p53-dependent apoptosis. An apoptosis-enhancing domain was identified in the C-terminal portion (amino acids 703–904) of MCM2. Furthermore, simultaneous treatment with FLV and doxorubicin extended the survival of SCID mice bearing 8047 leukemia cells expressing high levels of MCM2. Thus, depending on its subcellular localization, MCM2 plays different roles. It participates in DNA replication in the nucleus as shown previously, and enhances apoptosis in the cytoplasm