Cerebral blood flow autoregulation in early experimental S. pneumoniae meningitis.

We studied cerebral blood flow (CBF) autoregulation and intracranial pressure (ICP) during normo- and hyperventilation in a rat model of Streptococcus pneumoniae meningitis. Meningitis was induced by intracisternal injection of S. pneumoniae. Mean arterial blood pressure (MAP), ICP, cerebral perfusion pressure (CPP, defined as MAP - ICP), and laser-Doppler CBF were measured in anesthetized infected rats (n = 30) and saline-inoculated controls (n = 30). CPP was either incrementally reduced by controlled hemorrhage or increased by intravenous norepinephrine infusion. Twelve hours postinoculation, rats were studied solely during normocapnia, whereas rats studied after 24 h were exposed to either normocapnia or to acute hypocapnia. In infected rats compared with control rats, ICP was unchanged at 12 h but increased at 24 h postinoculation (not significant and P < 0.01, respectively); hypocapnia did not lower ICP compared with normocapnia. Twelve hours postinoculation, CBF autoregulation was lost in all infected rats but preserved in all control rats (P < 0.01). Twenty-four hours after inoculation, 10% of infected rats had preserved CBF autoregulation during normocapnia compared with 80% of control rats (P < 0.01). In contrast, 60% of the infected rats and 100% of the control rats showed an intact CBF autoregulation during hypocapnia (P < 0.05 for the comparison of infected rats at normocapnia vs. hypocapnia). In conclusion, CBF autoregulation is lost both at 12 and at 24 h after intracisternal inoculation of S. pneumoniae in rats. Impairment of CBF autoregulation precedes the increase in ICP, and acute hypocapnia may restore autoregulation without changing the ICP.     

Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans

The aim of this study was to determine whether inhibition of nitric oxide synthase (NOS) alters dynamic cerebral autoregulation in humans. Beat-to-beat blood pressure (BP) and cerebral blood flow (CBF) velocity (transcranial Doppler) were measured in eight healthy subjects in the supine position and during 60 degrees head-up tilt (HUT). NOS was inhibited by intravenous NG-monomethyl-L-arginine (L-NMMA) infusion. Dynamic cerebral autoregulation was quantified by transfer function analysis of beat-to-beat changes in BP and CBF velocity. Pressor effects of L-NMMA on cerebral hemodynamics were compared with those of phenylephrine infusion. In the supine position, L-NMMA increased mean BP from 83+/-3 to 94+/-3 mmHg (P < 0.01). However, CBF velocity remained unchanged. Consequently, cerebrovascular resistance index (CVRI) increased by 15% (P < 0.05). BP and CBF velocity variability and transfer function gain at the low frequencies of 0.07-0.20 Hz did not change with L-NMMA infusion. Similar changes in mean BP, CBF velocity, and CVRI were observed after phenylephrine infusion, suggesting that increase in CVRI after L-NMMA was mediated myogenically by increase in arterial pressure rather than a direct effect of cerebrovascular NOS inhibition. During baseline tilt without L-NMMA, steady-state BP increased and CBF velocity decreased. BP and CBF velocity variability at low frequencies increased in parallel by 277% and 217%, respectively (P < 0.05). However, transfer function gain remained unchanged. During tilt with L-NMMA, changes in steady-state hemodynamics and BP and CBF velocity variability as well as transfer gain and phase were similar to those without L-NMMA. These data suggest that inhibition of tonic production of NO does not appear to alter dynamic cerebral autoregulation in humans.     

A global mathematical model of the cerebral circulation in man

A mathematical model of the cerebral circulation has been formulated. It was based on non-linear equations of pulsatile fluid flow in distensible conduits and applied to a network simulating the entire cerebral vasculature, from the carotid and vertebral arteries to the sinuses and the jugular veins. The quasilinear hyperbolic system of equations was numerically solved using the two-step Lax-Wendroff scheme. The model's results were in good agreement with pressure and flow data recorded in humans during rest. The model was also applied to the study of autoregulation during arterial hypotension. A close relationship between cerebral blood flow (CBF) and capillary pressure was obtained. At arterial pressure of 80 mmHg, the vasodilation of the pial arteries was unable to maintain CBF at its control value. At the lower limit of autoregulation (60 mm Hg), CBF was maintained with a 25% increase of zero transmural pressure diameter of nearly the whole arterial network.     

Cerebral circulation during mild +Gz hypergravity by short-arm human centrifuge

We examined changes in cerebral circulation in 15 healthy men during exposure to mild +Gz hypergravity (1.5 Gz, head-to-foot) using a short-arm centrifuge. Continuous arterial pressure waveform (tonometry), cerebral blood flow (CBF) velocity in the middle cerebral artery (transcranial Doppler ultrasonography), and partial pressure of end-tidal carbon dioxide (ETco(2)) were measured in the sitting position (1 Gz) and during 21 min of exposure to mild hypergravity (1.5 Gz). Dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between beat-to-beat mean arterial pressure (MAP) and mean CBF velocity (MCBFV). Steady-state MAP did not change, but MCBFV was significantly reduced with 1.5 Gz (-7%). ETco(2) was also reduced (-12%). Variability of MAP increased significantly with 1.5 Gz in low (53%)- and high-frequency ranges (88%), but variability of MCBFV did not change in these frequency ranges, resulting in significant decreases in transfer function gain between MAP and MCBFV (gain in low-frequency range, -17%; gain in high-frequency range, -13%). In contrast, all of these indexes in the very low-frequency range were unchanged. Transfer from arterial pressure oscillations to CBF fluctuations was thus suppressed in low- and high-frequency ranges. These results suggest that steady-state global CBF was reduced, but dynamic cerebral autoregulation in low- and high-frequency ranges was improved with stabilization of CBF fluctuations despite increases in arterial pressure oscillations during mild +Gz hypergravity. We speculate that this improvement in dynamic cerebral autoregulation within these frequency ranges may have been due to compensatory effects against the reduction in steady-state global CBF.     

A multiscale 0-D/3-D approach to patient-specific adaptation of a cerebral autoregulation model for computational fluid dynamics studies of cardiopulmonary bypass

Neurological complication often occurs during cardiopulmonary bypass (CPB). One of the main causes is hypoperfusion of the cerebral tissue affected by the position of the cannula tip and diminished cerebral autoregulation (CA). Recently, a lumped parameter approach could describe the baroreflex, one of the main mechanisms of cerebral autoregulation, in a computational fluid dynamics (CFD) study of CPB. However, the cerebral blood flow (CBF) was overestimated and the physiological meaning of the variables and their impact on the model was unknown. In this study, we use a 0-D control circuit representation of the Baroreflex mechanism, to assess the parameters with respect to their physiological meaning and their influence on CBF. Afterwards the parameters are transferred to 3D-CFD and the static and dynamic behavior of cerebral autoregulation is investigated.     

Gene transfer of Cu/Zn SOD to cerebral vessels prevents FPI-induced CBF autoregulatory dysfunction

The goal of this study was to determine whether gene transfer of human copper-zinc (Cu/Zn) superoxide dismutase (SOD) has preventive effects on cerebral blood flow (CBF) autoregulatory dysfunction after fluid percussion injury (FPI). Rats subjected to FPI (2-2.5 atm) exhibited enhanced activity of reduced NADP (NADPH) oxidase in the cerebral vasculature. In line with these findings, the rats showed not only reduced vasodilation of the pial artery in response to calcitonin gene-related peptide and levcromakalim but also impaired autoregulatory vasodilation in response to acute hypotension. The FPI-induced hemodynamic alterations were significantly prevented by pretreatment with diphenyleneiodonium (10 micromol/l), an NAD(P)H oxidase inhibitor. Intracisternal application of recombinant adenovirus (100 microl of 1 x 10(10) pfu/ml)-encoding human Cu/Zn SOD 3 days before FPI prevented the impairment of vasodilation to hypotension and vasorelaxants, resulting in the restoration of CBF autoregulation. Our findings demonstrate that FPI-induced impairment of CBF autoregulation is closely related with NAD(P)H oxidase-derived superoxide anion, and these alterations can be prevented by the recombinant adenovirus-mediated transfer of human Cu/Zn SOD gene to the cerebral vasculature.     

Dynamic cardiorespiratory interaction during head-up tilt-mediated presyncope

In 28 healthy adults, we compared the dynamic interaction between respiration and cerebral autoregulation in 2 groups of subjects: those who did and did not develop presyncopal symptoms during 70 degrees passive head-up tilt (HUT), i.e., nonpresyncopal (23 subjects) and presyncopal (5 subjects). Airflow, CO2, cerebral blood flow velocity (CBF), ECG, and blood pressure (BP) were recorded. To determine whether influences of mean BP (MBP) and systolic SP (SBP) on CBF were altered in presyncopal subjects, coherencies and transfer functions between these variables and mean and peak CBF (CBFm and CBFp) were estimated. To determine the influence of end-tidal CO2 (ETco2) on CBF, the relative CO2 reactivity (%change in CBFm per mmHg change in ETco2) was calculated. We found that in presyncopal subjects before symptoms during HUT, coherence between SBP and CBFp was higher (P=0.02) and gains of transfer functions between BP (MBP and SBP) and CBFm were larger (MBP, P=0.01; SBP, P=0.01) in the respiratory frequency region. In the last 3 min before presyncope, presyncopals had a reduced relative CO2 reactivity (P=0.005), likely a consequence of the larger decrease in ETco2. We hypothesize that the CO2-mediated increase in resistance attenuates autoregulation such that the relationship between systemic and cerebral hemodynamics is enhanced. Our results suggest that an altered cardiorespiratory interaction involving cerebral hemodynamics may contribute in the cascade of events during tilt that culminate in unexplained syncope.     

Cerebral hemodynamics during arterial and CO(2) pressure changes: in vivo prediction by a mathematical model

The aim of this work was to analyze changes in cerebral hemodynamics and intracranial pressure (ICP) evoked by mean systemic arterial pressure (SAP) and arterial CO(2) pressure (Pa(CO(2))) challenges in patients with acute brain damage. The study was performed by means of a new simple mathematical model of intracranial hemodynamics, particularly aimed at routine clinical investigation. The model was validated by comparing its results with data from transcranial Doppler velocity in the middle cerebral artery (V(MCA)) and ICP measured in 44 tracings on 13 different patients during mean SAP and Pa(CO(2)) challenges. The validation consisted of individual identification of 6 parameters in all 44 tracings by means of a best fitting algorithm. The parameters chosen for the identification summarize the main aspects of intracranial dynamics, i.e., cerebrospinal fluid circulation, intracranial elastance, and cerebrovascular control. The results suggest that the model is able to reproduce the measured time patterns of V(MCA) and ICP in all 44 tracings by using values for the parameters that lie within the ranges reported in the pathophysiological literature. The meaning of parameter estimates is discussed, and comments on the main virtues and limitations of the present approach are offered.     

Alterations in autonomic function and cerebral hemodynamics to orthostatic challenge following a mountain marathon.

We examined potential mechanisms (autonomic function, hypotension, and cerebral hypoperfusion) responsible for orthostatic intolerance following prolonged exercise. Autonomic function and cerebral hemodynamics were monitored in seven athletes pre-, post- (<4 h), and 48 h following a mountain marathon [42.2 km; cumulative gain approximately 1,000 m; approximately 15 degrees C; completion time, 261 +/- 27 (SD) min]. In each condition, middle cerebral artery blood velocity (MCAv), blood pressure (BP), heart rate (HR), and cardiac output (Modelflow) were measured continuously before and during a 6-min stand. Measurements of HR and BP variability and time-domain analysis were used as an index of sympathovagal balance and baroreflex sensitivity (BRS). Cerebral autoregulation was assessed using transfer-function gain and phase shift in BP and MCAv. Hypotension was evident following the marathon during supine rest and on standing despite increased sympathetic and reduced parasympathetic control, and elevations in HR and cardiac output. On standing, following the marathon, there was less elevation in normalized low-frequency HR variability (P < 0.05), indicating attenuated sympathetic activation. MCAv was maintained while supine but reduced during orthostasis postmarathon [-10.4 +/- 9.8% pre- vs. -15.4 +/- 9.9% postmarathon (%change from supine); P < 0.05]; such reductions were related to an attenuation in BRS (r = 0.81; P < 0.05). Cerebral autoregulation was unchanged following the marathon. These findings indicate that following prolonged exercise, hypotension and postural reductions in autonomic function or baroreflex control, or both, rather than a compromise in cerebral autoregulation, may place the brain at risk of hypoperfusion. Such changes may be critical factors in collapse following prolonged exercise.     

Effects of Dexamethasone and Cox Inhibitors on Intracranial Pressure and Cerebral Perfusion in the Lipopolysaccharide Treated Rats with Hyperammonemia

IntroductionSystemic inflammation may affect the brain by aggravating the stage of encephalopathy and increasing intracranial pressure (ICP) especially if liver insufficiency with hyperammonemia is present. The aim of this study was to determine if the influence of concomitant hyperammonemia and lipopolysaccharide (LPS) on the brain can be prevented by dexamethasone and cyclooxygenase (COX) inhibitors.MethodFifty-four male Wistar rats, 6 in each group, were divided into the following groups: Saline+saline; LPS (2mg/kg)+saline; LPS+indomethacin (10mg/kg); LPS+diclofenac (10mg/kg); LPS+dexamethasone (2mg/kg) in experiment A. Experiment-B included the following groups: LPS+NH3 (140μmol/kg/min)+saline; LPS+NH3+indomethacin; LPS+NH3+diclofenac and LPS+NH3+dexamethasone. ICP was monitored via a catheter placed in cisterna magna and changes in CBF were recorded by laser Doppler flowmetry.ResultsLPS with and without NH3 induced a similar increase in plasma 6-keto-prostaglandin-F_1α (6-keto-PGF_1α) concentration together with a concomitant rise in CBF and ICP. Indomethacin and diclofenac prevented the increase in ICP by LPS alone, and with the addition of NH3 the increase in both CBF and ICP, which was associated with a decrease in 6-keto-PGF_1α. Dexamethasone only reduced the LPS induced increase in ICP but not CBF, and partly the 6-keto-PGF_1α plasma concentration in the combined setup.ConclusionThese data indicate that activation of cycloooxygenases is of central importance for development of cerebral hyperemia and high ICP during concomitant systemic inflammation and hyperammonemia.     

Osmolality of Cerebrospinal Fluid from Patients with Idiopathic Intracranial Hypertension (IIH)

Introduction

Idiopathic intracranial hypertension (IIH) is a disorder of increased intracranial fluid pressure (ICP) of unknown etiology. This study aims to investigate osmolality of cerebrospinal fluid (CSF) from patients with IIH.

Methods

We prospectively collected CSF from individuals referred on suspicion of IIH from 2011–2013. Subjects included as patients fulfilled Friedman and Jacobson’s diagnostic criteria for IIH. Individuals in whom intracranial hypertension was refuted were included as controls. Lumbar puncture with ICP measurement was performed at inclusion and repeated for patients after three months of treatment. Osmolality was measured with a Vapor Pressure Osmometer.

Results

We collected 90 CSF samples from 38 newly diagnosed patients and 28 controls. At baseline 27 IIH-samples and at 3 months follow-up 35 IIH-samples were collected from patients. We found no significant differences in osmolality between 1) patients at baseline and controls (p = 0. 86), 2) patients at baseline and after 3 months treatment (p = 0.97), and 3) patients with normalized pressure after 3 months and their baseline values (p = 0.79). Osmolality in individuals with normal ICP from 6–25 cmH₂O (n = 41) did not differ significantly from patients with moderately elevated ICP from 26–45 cmH₂O (n = 21) (p = 0.86) and patients with high ICP from 46–70 cmH₂O (n = 4) (p = 0.32), respectively. There was no correlation between osmolality and ICP, BMI, age and body height, respectively. Mean CSF osmolality was 270 mmol/kg (± 1 SE, 95% confidence interval 267–272) for both patients and controls.

Conclusions

CSF osmolality was normal in patients with IIH, and there was no relation to treatment, ICP, BMI, age and body height. Mean CSF osmolality was 270 mmol/kg and constitutes a reference for future studies. Changes in CSF osmolality are not responsible for development of IIH. Other underlying pathophysiological mechanisms must be searched.     

A severe vicious cycle in uncontrolled subarachnoid hemorrhage: the effects on cerebral blood flow and hemodynamic responses upon intracranial hypertension

In subarachnoid hemorrhage (SAH), Cushing postulated that the increase in systemic arterial pressure (SAP) in response to elevation of intracranial pressure (ICP) was beneficial to cerebral perfusion. However, in uncontrolled SAH, the increased SAP may cause more bleeding into the subarachnoid space and further increase the ICP. We created an animal model to simulate SAH by connecting a femoral arterial catheter to the subarachnoid space. The global cerebral blood flow (CBF) was measured with a venous outflow method. The purposes were to observe the CBF change under the simulated SAH, and to evaluate the effects of an adrenergic blocker and a vasodilator. In addition, spectral analysis of the aortic pressure and flow was employed for the analysis of hemodynamic changes at various ICP levels. When the femoral arterial blood was allowed to flow into the subarachnoid space, the ICP was elevated. The Cushing response to increased ICP caused an increase in SAP. A vicious cycle was generated between ICP and SAP. The CBF under the vicious cycle was greatly depressed. The dog developed pulmonary edema (PE) within 5 mins. An alpha-adrenergic blocker (phentolamine) and a vasodilator (nitroprusside) were beneficial to the reduction of SAP and ICP, improvement of CBF, and prevention of PE. Hemodynamic analysis revealed that graded increases in ICP caused increases in SAP, total peripheral resistance, arterial impedance, and pulse reflection with decreases in stroke volume, cardiac output and arterial compliance. The hemodynamic changes may contribute to acute left ventricular failure that leads to pressure and volume loading in the lung circulation, and finally acute PE.     

Cerebral arteriolar structure and function in pinealectomized rats

We examined cerebral arteriolar structure and autoregulation of cerebral blood flow (CBF) in control (n = 8), sham-operated (n = 8), pinealectomized (n = 10), and pinealectomized plus melatonin-treated (0.51 +/- 0.01 mg x kg(-1) x day(-1) in drinking water, n = 9) young Wistar rats. The lower limit of CBF autoregulation (LLCBF) was determined by measurement of CBF (in arbitrary units, laser Doppler) during stepwise hypotensive hemorrhage; the arteriolar internal diameter (ID; in microm, cranial window) was also measured. Measurements of ID were repeated during a second stepwise hypotension after smooth muscle cell deactivation (67 mmol/l EDTA). The cross-sectional area (CSA) was measured by histometry. CSA and EDTA-induced vasodilatation decreased after pinealectomy (517 +/- 21 vs. 819 +/- 40 microm(2) in sham and 829 +/- 55 microm(2) in control, P < 0.05, and 81 +/- 4 vs. 102 +/- 5 microm in sham and 104 +/- 4 microm in control, P < 0.05, respectively) and were restored by melatonin (924 +/- 39 microm(2) and 102 +/- 5 microm, respectively). These results suggest that melatonin deprival makes the arteriolar wall thinner and stiffer. However, these changes had little effect on LLCBF. In conclusion, pinealectomy of young rats induces atrophy and decreases distensibility of the cerebral arteriolar wall; these effects are prevented by melatonin. They do not modify LLCBF.     

Intracranial pressure. III. Trial generalized theory]

The authors reported previously an elementary mathematical model of intracranial pressure (ICP) as well as result from an experimental verification of the model. The experimental tests revealed that certain factors had been neglected in the theoretical formation, and the present article offers an expanded version of model which takes into account those factors: changes in the formation of the CSF as a function of ICP; cerebral vasomotricity; cortical and sinusal venous pressures, and variations of the filtration coefficient of the subarachnoidal spaces. A generalized mathematical model of ICP, in the form of four equations, is proposed. The major aspects of both normal and pathological ICP are studied in the light of this model, and are integrated into a generalized theory.     

Implication of adenosine A2A receptors in hypotension-induced vasodilation and cerebral blood flow autoregulation in rat pial arteries

This study aimed to evaluate the role for adenosine A2A receptors in the autoregulatory vasodilation to hypotension in relation with cerebral blood flow (CBF) autoregulation in rat pial arteries. Changes in pial artery diameters were observed directly through a closed cranial window. Vasodilation induced by adenosine was markedly suppressed by ZM 241385 (1 micromol/l, A2A antagonist) and alloxazine (1 micromol/l, A2B antagonist), but not by 8-cyclopentyltheophylline (CPT, 1 micromol/l, A1 antagonist). CGS-21680-induced vasodilation was more strongly inhibited by ZM 241385 (25.3-fold; P<0.05) than by alloxazine. In contrast, 5'-N-ethylcarboxamido-adenosine (NECA)-induced vasodilation was more prominently suppressed by alloxazine (12.0-fold; P<0.001) than by ZM 241385. The autoregulatory vasodilation in response to acute hypotension of the pial arteries was significantly suppressed by ZM 241385, but not by CPT and alloxazine. Consistent with this finding, the lower limit of CBF autoregulation significantly shifted to a higher blood pressure by 1 micromol/l of ZM 241385 (53.0+/-3.9 mm Hg to 69.2+/-2.9 mm Hg, P<0.01) and 10 micromol/l of glibenclamide (54.7+/-6.5 mm Hg to 77.9+/-4.2 mm Hg, P<0.001), but not by CPT and alloxazine. Thus, it is suggested that adenosine-induced vasodilation of the rat pial artery is mediated via activation of adenosine A2A and A2B receptors, but not by A1 subtype, and activation of adenosine A2A receptor preferentially contributes to the autoregulatory vasodilation via activation of ATP-sensitive K+ channels in response to hypotension and maintenance of CBF autoregulation.     

Observation of multiple folding pathways of beta-hairpin trpzip2 from independent continuous folding trajectories

Motivation: After 10-year investigations, the folding mechanismsof β-hairpins are still under debate. Experiments stronglysupport zip-out pathway, while most simulations prefer the hydrophobiccollapse model (including middle-out and zip-in pathways). Inthis article, we show that all pathways can occur during thefolding of β-hairpins but with different probabilities.The zip-out pathway is the most probable one. This is in agreementwith the experimental results. We came to our conclusions by38 100-ns room-temperature all-atom molecular dynamics simulationsof the β-hairpin trpzip2. Our results may help to clarifythe inconsistencies in the current pictures of β-hairpinfolding mechanisms. Contact: yxiao{at}mail.hust.edu.cn Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Anna Tramontano     

Nitric oxide, prostaglandins, and impaired cerebral blood flow autoregulation in group B streptococcal neonatal meningitis

Impaired autoregulation of cerebral blood flow (CBF) contributes to CNS damage during neonatal meningitis. We tested (i) the hypothesis that cerebrovascular autoregulation is impaired during early onset group B streptococcal (GBS) meningitis, (ii) whether this impairment is regulated by vasoactive mediators such as prostaglandins and (or) nitric oxide (NO), and (iii) whether this impairment is preventable by specific and (or) nonspecific inhibitors: dexamethasone, ibuprofen, and Nomega-nitro-L-arginine, a NO inhibitor. Sterile saline or 10(9) colony-forming units (cfu) of heat-killed GBS was injected into the cerebral ventricle of newborn piglets. CBF autoregulation was determined by altering cerebral perfusion pressure (CPP) with balloon-tipped catheters placed in the aorta. GBS produced a narrow range of CBF autoregulation due to an impairment at the upper limit of CPP. We report that in vivo in the early stages (first 2 h) of induced GBS inflammation (i) GBS impairs the upper limit of cerebrovascular autoregulation; (ii) ibuprofen, dexamethasone, and Nomega-nitro-L-arginine not only prevent this GBS-induced autoregulatory impairment but improve the range of cerebrovascular autoregulation; (iii) these autoregulatory changes do not involve circulating cerebral prostanoids; and (iv) the observed changes correlate with the induction of NO synthase gene expression. Thus, acute early onset GBS-induced impairment of the upper limit of CBF autoregulation can be correlated with increases of NO synthase production, suggesting that NO is a vasoactive mediator of CBF.     

Deterioration of cerebral autoregulation during orthostatic stress: insights from the frequency domain

To determine whether dynamiccerebral autoregulation is impaired during orthostatic stress, cerebralblood flow (CBF) velocity in the middle cerebral artery (transcranialDoppler) and mean arterial pressure (MAP; Finapres) were measuredcontinuously in 12 healthy subjects during ramped maximal lower bodynegative pressure (LBNP) to presyncope. Velocity andpressure were averaged over 6-min periods of stable data at rest andduring LBNP to examine steady-state cerebral hemodynamics. Beat-to-beatvariability of velocity and pressure were quantified by a "variationindex" (oscillatory amplitude/steady-state mean value) and by powerspectral analysis. The dynamic relationship between changes in pressureand velocity was evaluated by the estimates of transfer and coherencefunction. The results of the study were as follows.Steady-state MAP remained relatively constant during LBNP, whereas CBFvelocity decreased progressively by 6, 15, and 21% at 30,40, and 50 mmHg LBNP, respectively(P < 0.05 compared withbaseline). At the maximal level of LBNP (30 s beforepresyncope) MAP decreased by 9.4% in association with a prominentreduction in velocity by 24% (P < 0.05 compared with baseline). The variation index of pressure increasedsignificantly from 3.8 ± 0.3% at baseline to 4.5 ± 0.6% at50 mmHg LBNP in association with an increase in the variation index of velocity from 6.0 ± 0.6 to 8.4 ± 0.7%(P < 0.05). Consistently, the low-(0.07-0.20 Hz) and high-frequency (0.20-0.30 Hz) power ofvariations in pressure and velocity increased significantly at highlevels of LBNP (P < 0.05) inassociation with an increase in transfer function gain (24% at50 mmHg, P < 0.05). We conclude that the damping effects ofautoregulation on variations in CBF velocity are diminishedduring orthostatic stress in association with substantial falls insteady-state CBF velocity. We suggest that these changes may contributein part to the development of presyncope.

     

Model-based deconvolution of genome-wide DNA binding

Motivation: Chromatin immunoprecipitation followed by hybridizationto a genomic tiling microarray (ChIP-chip) is a routinely usedprotocol for localizing the genomic targets of DNA-binding proteins.The resolution to which binding sites in this assay can be identifiedis commonly considered to be limited by two factors: (1) theresolution at which the genomic targets are tiled in the microarrayand (2) the large and variable lengths of the immunoprecipitatedDNA fragments. Results: We have developed a generative model of binding sitesin ChIP-chip data and an approach, MeDiChI, for efficientlyand robustly learning that model from diverse data sets. Wehave evaluated MeDiChI's performance using simulated data, aswell as on several diverse ChIP-chip data sets collected onwidely different tiling array platforms for two different organisms(Saccharomyces cerevisiae and Halobacterium salinarium NRC-1).We find that MeDiChI accurately predicts binding locations toa resolution greater than that of the probe spacing, even foroverlapping peaks, and can increase the effective resolutionof tiling array data by a factor of 5x or better. Moreover,the method's performance on simulated data provides insightsinto effectively optimizing the experimental design for increasedbinding site localization accuracy and efficacy. Availability: MeDiChI is available as an open-source R package,including all data, from http://baliga.systemsbiology.net/medichi. Contact: dreiss{at}systemsbiology.org Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Martin Bishop