Noninvasive determination of intraocular pressure (IOP) in nonsedated mice of 5 different inbred strains

BACKGROUND: Noninvasive intraocular pressure (IOP) measurement in mice is critically important for understanding the pathophysiology of glaucoma. Rebound tonometry is one of the methods that can be used for obtaining such measurements. We evaluated the ability of the rebound tonometer (RT) to determine IOP differences among various mouse strains and whether differences in corneal thickness may affect IOP measurements in these animals. MATERIALS AND METHODS: Five different commonly used mouse strains (BALB/C, CBA/CAHN, AKR/J, CBA/J, and 129P3/J) were used. IOP was measured in eyes from 12 nonsedated animals (6 male and 6 female) from each strain at 2 to 3 months of age using the RT. IOPs were measured in all animals, on 2 different days between 10 AM and 12 PM. Subsequently, a number of eyes from each strain were cannulated to provide a calibration curve specific for that strain. Tonometer readings for all strains were converted to apparent IOP values using the calibration data obtained from the calibration curve of the respective strain. For comparison purposes, IOP values were also obtained using the C57BL/6 calibration data previously reported. IOP for the 5 strains, male and female animals, and the different occasion of measurement were compared using repeat measures analysis of variance. The central corneal thickness (CCT) of another group of 8 male animals from each of the 5 strains was also measured using an optical low coherence reflectometry (OLCR) pachymeter modified for use with mice. CCT values were correlated to mean IOPs of male animals and to the slopes and intercept of individual strain calibration curves. RESULTS: Noninvasive IOP measurements confirm that the BALB/C strain has lower and the CBA/CAHN has higher relative IOPs than other mouse strains while the AKR/J, the CBA/J, and the 129P3/J strains have intermediate IOPs. There is a very good correlation of apparent IOP values obtained by RT with previously reported true IOPs obtained by cannulation. There was a small but statistically significant difference in IOP between male and female animals in 2 strains (129P3/J and AKR/J) with female mice having higher relative IOPs. No correlation between CCT and IOP was detected. CCT did not correlate with any of the constants describing the calibration curves in the various strains. CONCLUSIONS: Noninvasive IOP measurement in mice using the RT can be used to help elucidate IOP phenotype, after prior calibration of the tonometer. CCT has no effect on mouse IOP measurements using the RT.

Managing chronic whiplash associated pain with a combination of low-dose opioid (remifentanil) and NMDA-antagonist (ketamine)

The aim was to investigate the efficacy of a combination of low-dose remifentanil (REMI) and ketamine (KET) compared to the single drugs and placebo (P) on whiplash associated pain (WAD) in a double-blind, randomized, placebo-controlled, cross-over study. Twenty patients with chronic (>1 year) WAD were included. Four different drug combinations were tested in four sessions: placebo/placebo (P/P), placebo/remifentanil (P/REMI), ketamine/placebo (KET/P) and ketamine/remifentanil (KET/REMI). Target concentrations were 1 and 2ng/ml (stepwise) for remifentanil and 100ng/ml for ketamine. Habitual pain intensity was assessed on a visual analogue scale (VAS). Experimental pain was assessed with electrical stimulation (single and repeated) of tibialis anterior (TA) muscle, pressure pain algometry applied over infraspinatus (IS) and TA muscles and VAS scores after intramuscular hypertonic saline infusion in TA. KET/REMI significantly reduced habitual pain. KET/REMI infused at low REMI target concentration (1ng/ml) significantly elevated electrical intramuscular pain thresholds (single and repeated). Pain thresholds to electrical stimulation were similarly increased by both P/REMI and KET/REMI at 2ng/ml target concentration. Pressure pain thresholds were increased by both KET/REMI and P/REMI. VAS-scores after intramuscular saline were also similarly decreased by both REMI combinations. Seven out of 20 subjects were non-responders (<50% pain relief). No correlation was found between effects on spontaneous pain and experimental pain. KET/REMI showed an analgesic effect on habitual pain. Experimental pain was attenuated by both combinations containing the opioid, however, KET seemed to enhance the effect of REMI on electrical pain thresholds when a low REMI target concentration was used.

Influence of granulocytes on brain edema, intracranial pressure, and cerebrospinal fluid concentrations of lactate and protein in experimental meningitis

Brain water content (brain edema), intracranial pressure, and cerebrospinal fluid (CSF) concentrations of lactate and protein increased significantly during 24 h of experimental meningitis due to Streptococcus pneumoniae, but changes were similar in normal and neutropenic rabbits. In sterile meningitis induced by N-formyl-methionyl-leucyl-phenyl-alanine (fMLP), low and high doses of fMLP were equally effective in inducing CSF pleocytosis, whereas only high doses of fMLP caused brain edema. High doses of fMLP injected intracisternally during pneumococcal meningitis also increased brain water content. The fMLP did not significantly increase intracranial pressure or CSF concentrations of lactate or protein in sterile or pneumococcal meningitis, nor did it cause brain edema in neutropenic animals. Thus, granulocytes may contribute to brain edema during meningitis if adequately stimulated, but intracranial pressure and CSF protein and lactate concentrations appear independent of granulocytes. Stimulation does not appear to occur early in meningitis, when granulocytes were without effect on brain edema.

Norepinephrine to increase blood pressure in endotoxaemic pigs is associated with improved hepatic mitochondrial respiration

ABSTRACT: INTRODUCTION: Low blood pressure, inadequate tissue oxygen delivery and mitochondrial dysfunction have all been implicated in the development of sepsis-induced organ failure. This study evaluated the effect on liver mitochondrial function of using norepinephrine to increase blood pressure in experimental sepsis. METHODS: Thirteen anaesthetized pigs received endotoxin (Escherichia coli lipopolysaccharide B0111:B4; 0.4 mug/kg per hour) and were subsequently randomly assigned to norepinephrine treatment or placebo for 10 hours. Norepinephrine dose was adjusted at 2-hour intervals to achieve 15 mmHg increases in mean arterial blood pressure up to 95 mmHg. Systemic (thermodilution) and hepatosplanchnic (ultrasound Doppler) blood flow were measured at each step. At the end of the experiment, hepatic mitochondrial oxygen consumption (high-resolution respirometry) and citrate synthase activity (spectrophotometry) were assessed. RESULTS: Mean arterial pressure (mmHg) increased only in norepinephrine-treated animals (from 73 [median; range 69 to 81] to 63 [60 to 68] in controls [P = 0.09] and from 83 [69 to 93] to 96 [86 to 108] in norepinephrine-treated animals [P = 0.019]). Cardiac index and systemic oxygen delivery (DO2) increased in both groups, but significantly more in the norepinephrine group (P < 0.03 for both). Cardiac index (ml/min per.kg) increased from 99 (range: 72 to 112) to 117 (110 to 232) in controls (P = 0.002), and from 107 (84 to 132) to 161 (147 to 340) in norepinephrine-treated animals (P = 0.001). DO2 (ml/min per.kg) increased from 13 (range: 11 to 15) to 16 (15 to 24) in controls (P = 0.028), and from 16 (12 to 19) to 29 (25 to 52) in norepinephrine-treated animals (P = 0.018). Systemic oxygen consumption (systemic VO2) increased in both groups (P < 0.05), whereas hepatosplanchnic flows, DO2 and VO2 remained stable. The hepatic lactate extraction ratio decreased in both groups (P = 0.05). Liver mitochondria complex I-dependent and II-dependent respiratory control ratios were increased in the norepinephrine group (complex I: 3.5 [range: 2.1 to 5.7] in controls versus 5.8 [4.8 to 6.4] in norepinephrine-treated animals [P = 0.015]; complex II: 3.1 [2.3 to 3.8] in controls versus 3.7 [3.3 to 4.6] in norepinephrine-treated animals [P = 0.09]). No differences were observed in citrate synthase activity. CONCLUSION: Norepinephrine treatment during endotoxaemia does not increase hepatosplanchnic flow, oxygen delivery or consumption, and does not improve the hepatic lactate extraction ratio. However, norepinephrine increases the liver mitochondria complex I-dependent and II-dependent respiratory control ratios. This effect was probably mediated by a direct effect of norepinephrine on liver cells.

Pulmonary-artery pressure and exhaled nitric oxide in Bolivian and Caucasian high altitude dwellers

There is evidence that high altitude populations may be better protected from hypoxic pulmonary hypertension than low altitude natives, but the underlying mechanism is incompletely understood. In Tibetans, increased pulmonary respiratory NO synthesis attenuates hypoxic pulmonary hypertension. It has been speculated that this mechanism may represent a generalized high altitude adaptation pattern, but direct evidence for this speculation is lacking. We therefore measured systolic pulmonary-artery pressure (Doppler chocardiography) and exhaled nitric oxide (NO) in 34 healthy, middle-aged Bolivian high altitude natives and in 34 age- and sex-matched, well-acclimatized Caucasian low altitude natives living at high altitude (3600 m). The mean+/-SD systolic right ventricular to right atrial pressure gradient (24.3+/-5.9 vs. 24.7+/-4.9 mmHg) and exhaled NO (19.2+/-7.2 vs. 22.5+/-9.5 ppb) were similar in Bolivians and Caucasians. There was no relationship between pulmonary-artery pressure and respiratory NO in the two groups. These findings provide no evidence that Bolivian high altitude natives are better protected from hypoxic pulmonary hypertension than Caucasian low altitude natives and suggest that attenuation of pulmonary hypertension by increased respiratory NO synthesis may not represent a universal adaptation pattern in highaltitude populations.

Respiratory nitric oxide and pulmonary artery pressure in children of aymara and European ancestry at high altitude

Invasive studies suggest that healthy children living at high altitude display pulmonary hypertension, but the data to support this assumption are sparse. Nitric oxide (NO) synthesized by the respiratory epithelium regulates pulmonary artery pressure, and its synthesis was reported to be increased in Aymara high-altitude dwellers. We hypothesized that pulmonary artery pressure will be lower in Aymara children than in children of European ancestry at high altitude, and that this will be related to increased respiratory NO. We therefore compared pulmonary artery pressure and exhaled NO (a marker of respiratory epithelial NO synthesis) between large groups of healthy children of Aymara (n = 200; mean +/- SD age, 9.5 +/- 3.6 years) and European ancestry (n = 77) living at high altitude (3,600 to 4,000 m). We also studied a group of European children (n = 29) living at low altitude. The systolic right ventricular to right atrial pressure gradient in the Aymara children was normal, even though significantly higher than the gradient measured in European children at low altitude (22.5 +/- 6.1 mm Hg vs 17.7 +/- 3.1 mm Hg, p < 0.001). In children of European ancestry studied at high altitude, the pressure gradient was 33% higher than in the Aymara children (30.0 +/- 5.3 mm Hg vs 22.5 +/- 6.1 mm Hg, p < 0.0001). In contrast to what was expected, exhaled NO tended to be lower in Aymara children than in European children living at the same altitude (12.4 +/- 8.8 parts per billion [ppb] vs 16.1 +/- 11.1 ppb, p = 0.06) and was not related to pulmonary artery pressure in either group. Aymara children are protected from hypoxic pulmonary hypertension at high altitude. This protection does not appear to be related to increased respiratory NO synthesis.

Salt sensitivity of children with low birth weight

Compromised intrauterine fetal growth leading to low birth weight (<2500 g) is associated with adulthood renal and cardiovascular disease. The aim of this study was to assess the effect of salt intake on blood pressure (salt sensitivity) in children with low birth weight. White children (n=50; mean age: 11.3+/-2.1 years) born with low (n=35) or normal (n=15) birth weight and being either small or appropriate for gestational age (n=25 in each group) were investigated. The glomerular filtration rate was calculated using the Schwartz formula, and renal size was measured by ultrasound. Salt sensitivity was assigned if mean 24-hour blood pressure increased by >or=3 mm Hg on a high-salt diet as compared with a controlled-salt diet. Baseline office blood pressure was higher and glomerular filtration rate lower in children born with low birth weight as compared with children born at term with appropriate weight (P<0.05). Salt sensitivity was present in 37% and 47% of all of the low birth weight and small for gestational age children, respectively, higher even than healthy young adults from the same region. Kidney length and volume (both P<0.0001) were reduced in low birth weight children. Salt sensitivity inversely correlated with kidney length (r(2)=0.31; P=0.005) but not with glomerular filtration rate. We conclude that a reduced renal mass in growth-restricted children poses a risk for a lower renal function and for increased salt sensitivity. Whether the changes in renal growth are causative or are the consequence of the same abnormal "fetal programming" awaits clarification.

Electron microscopy of high pressure frozen samples: bridging the gap between cellular ultrastructure and atomic resolution

Transmission electron microscopy has provided most of what is known about the ultrastructural organization of tissues, cells, and organelles. Due to tremendous advances in crystallography and magnetic resonance imaging, almost any protein can now be modeled at atomic resolution. To fully understand the workings of biological "nanomachines" it is necessary to obtain images of intact macromolecular assemblies in situ. Although the resolution power of electron microscopes is on the atomic scale, in biological samples artifacts introduced by aldehyde fixation, dehydration and staining, but also section thickness reduces it to some nanometers. Cryofixation by high pressure freezing circumvents many of the artifacts since it allows vitrifying biological samples of about 200 mum in thickness and immobilizes complex macromolecular assemblies in their native state in situ. To exploit the perfect structural preservation of frozen hydrated sections, sophisticated instruments are needed, e.g., high voltage electron microscopes equipped with precise goniometers that work at low temperature and digital cameras of high sensitivity and pixel number. With them, it is possible to generate high resolution tomograms, i.e., 3D views of subcellular structures. This review describes theory and applications of the high pressure cryofixation methodology and compares its results with those of conventional procedures. Moreover, recent findings will be discussed showing that molecular models of proteins can be fitted into depicted organellar ultrastructure of images of frozen hydrated sections. High pressure freezing of tissue is the base which may lead to precise models of macromolecular assemblies in situ, and thus to a better understanding of the function of complex cellular structures.

Effects of a low dose infusion of racemic and S-ketamine on the nociceptive withdrawal reflex in standing ponies

OBJECTIVE: To investigate the effect of plasma concentrations obtained by a low dose constant rate infusion (CRI) of racemic ketamine or S-ketamine on the nociceptive withdrawal reflex (NWR) in standing ponies. STUDY DESIGN: Prospective, blinded, cross-over study. ANIMALS: Six healthy 5-year-old Shetland ponies. METHODS: Ponies received either 0.6 mg kg(-1) racemic ketamine (group RS) or 0.3 mg kg(-1) S-ketamine (group S) intravenously (IV), followed by a CRI of 20 microg kg(-1)minute(-1) racemic ketamine (group RS) or 10 microg kg(-1)minute(-1) S-ketamine (group S) for 59 minutes. The NWR was evoked by transcutaneous electrical stimulation of a peripheral nerve before drug administration, 15 and 45 minutes after the start of the bolus injection and 15 minutes after the end of the CRI. Electromyographic responses were recorded and analysed. Arterial blood was collected before stimulation and plasma concentrations of ketamine and norketamine were measured enantioselectively using capillary electrophoresis. Ponies were video recorded and monitored to assess drug effects on behaviour, heart rate (HR), mean arterial blood pressure (MAP) and respiratory rate. RESULTS: The NWR was significantly depressed in group RS at plasma concentrations between 20 and 25 ng mL(-1) of each enantiomer. In group S, no significant NWR depression could be observed; plasma concentrations of S-ketamine (9-15 ng mL(-1)) were lower, compared to S-ketamine concentrations in group RS, although this difference was not statistically significant. Minor changes in behaviour, HR and MAP only occurred within the first 5-10 minutes after bolus drug administration in both groups. CONCLUSION: Antinociceptive activity in standing ponies, demonstrated as a depression of the NWR, could only be detected after treatment with racemic ketamine. S-ketamine may have lacked this effect as a result of lower plasma concentrations, a more rapid metabolism or a lower potency of S-ketamine in Equidae so further investigation is necessary.

Evaluation of anesthesia recovery quality after low-dose racemic or S-ketamine infusions during anesthesia with isoflurane in horses

OBJECTIVE: To compare anesthesia recovery quality after racemic (R-/S-) or S-ketamine infusions during isoflurane anesthesia in horses. ANIMALS: 10 horses undergoing arthroscopy. PROCEDURES: After administration of xylazine for sedation, horses (n = 5/group) received R-/S-ketamine (2.2 mg/kg) or S-ketamine (1.1 mg/kg), IV, for anesthesia induction. Anesthesia was maintained with isoflurane in oxygen and R-/S-ketamine (1 mg/kg/h) or S-ketamine (0.5 mg/kg/h). Heart rate, invasive mean arterial pressure, and end-tidal isoflurane concentration were recorded before and during surgical stimulation. Arterial blood gases were evaluated every 30 minutes. Arterial ketamine and norketamine enantiomer plasma concentrations were quantified at 60 and 120 minutes. After surgery, horses were kept in a padded recovery box, sedated with xylazine, and video-recorded for evaluation of recovery quality by use of a visual analogue scale (VAS) and a numeric rating scale. RESULTS: Horses in the S-ketamine group had better numeric rating scale and VAS values than those in the R-/S-ketamine group. In the R-/S-ketamine group, duration of infusion was positively correlated with VAS value. Both groups had significant increases in heart rate and mean arterial pressure during surgical stimulation; values in the R-/S-ketamine group were significantly higher than those of the S-ketamine group. Horses in the R-/S-ketamine group required slightly higher end-tidal isoflurane concentration to maintain a surgical plane of anesthesia. Moderate respiratory acidosis and reduced oxygenation were evident. The R-norketamine concentrations were significantly lower than S-norketamine concentrations in the R-/S-ketamine group. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with R-/S-ketamine, anesthesia recovery was better with S-ketamine infusions in horses.

Tunnelled versus straight intravitreal injection: intraocular pressure changes, vitreous reflux, and patient discomfort

PURPOSE: To compare tunnelled scleral intravitreal injection with straight scleral intravitreal injection concerning short-term intraocular pressure (IOP) changes, occurrence and amount of vitreous reflux, and patient discomfort. METHODS: Sixty patients were randomly allocated to two groups (tunnelled intravitreal injection and straight intravitreal injection). IOP was measured before and directly (<1 minute) after the injection of 0.05 mL of an antivascular endothelial growth factor agent and then every 5 minutes until IOP was <30 mmHg. Occurrence and amount of vitreous reflux were recorded. Patient discomfort during injection was assessed with a Wong-Baker faces pain rating scale. RESULTS: IOP (mmHg +/- SD) increased significantly directly after injection to 35.97 +/- 8.13 (tunnelled intravitreal injection) and 30.19 +/- 12.14 (straight intravitreal injection). These pressure spikes differed significantly between both groups (P = 0.01, mean difference: -7.11). Five minutes after injection, there was no significant difference in IOP increase between the groups. All IOP measurements were <30 mmHg after 15 minutes. Occurrence and amount of vitreous reflux were significantly higher with straight intravitreal injection. There was no significant difference in Wong-Baker faces pain rating scale score between both groups. CONCLUSION: Tunnelled intravitreal injection seems to be the technique of choice for low-volume intravitreal injection (0.05 mL). There is neither a difference in patient discomfort nor a difference in IOP increase 5 minutes after injection between both groups. Significantly less vitreous reflux with tunnelled intravitreal injection should lead to less postinjectional drug loss.

Strong Down-Valley Low-Level Jets over the Atacama Desert: Observational Characterization

The near-surface wind and temperature regime at three points in the Atacama Desert of northern Chile is described using two-year multi-level measurements from 80-m towers located in an altitude range between 2100 and 2700 m ASL. The data reveal the frequent development of strong nocturnal drainage flows at all sites. Down-valley nose-shaped wind speed profiles are observed with maximum values occurring at heights between 20 m and 60 m AGL. The flow intensity shows considerable inter-daily variability and a seasonal modulation of maximum speeds, which in the cold season can attain hourly average values larger than 20 m s−1. Turbulent mixing appears significant over the full tower layer, affecting the curvature of the nighttime temperature profile and possibly explaining the observed increase of surface temperatures in the down-valley direction. Nocturnal valley winds and temperatures are weakly controlled by upper-air conditions observed at the nearest aerological station. Estimates of terms in the momentum budget for the development and the quasi-stationary phases of the down-valley flows suggest that the pressure gradient force due to the near-surface cooling along the sloping valley axes plays an important role in these drainage flows. A scale for the jet nose height of equilibrium turbulent down-slope jets is proposed, based on surface friction velocity and surface inversion intensity. At one of the sites this scale explains about 70% of the case-to-case observed variance of jet nose heights. Further modeling and observational work is needed, however, in order to better define the dynamics, extent and turbulence structure of this flow system, which has significant wind-energy, climatic and environmental implications.

Reciprocal relationship between left ventricular filling pressure and the recruitable human coronary collateral circulation

AIMS The aim of our study in patients with coronary artery disease (CAD) and present, or absent, myocardial ischaemia during coronary occlusion was to test whether (i) left ventricular (LV) filling pressure is influenced by the collateral circulation and, on the other hand, that (ii) its resistance to flow is directly associated with LV filling pressure. METHODS AND RESULTS In 50 patients with CAD, the following parameters were obtained before and during a 60 s balloon occlusion: LV, aortic (Pao) and coronary pressure (Poccl), flow velocity (Voccl), central venous pressure (CVP), and coronary flow velocity after coronary angioplasty (V(Ø-occl)). The following variables were determined and analysed at 10 s intervals during occlusion, and at 60 s of occlusion: LV end-diastolic pressure (LVEDP), velocity-derived (CFIv) and pressure-derived collateral flow index (CFIp), coronary collateral (Rcoll), and peripheral resistance index to flow (Rperiph). Patients with ECG signs of ischaemia during coronary occlusion (insufficient collaterals, n = 33) had higher values of LVEDP over the entire course of occlusion than those without ECG signs of ischaemia during occlusion (sufficient collaterals, n = 17). Despite no ischaemia in the latter, there was an increase in LVEDP from 20 to 60 s of occlusion. In patients with insufficient collaterals, CFIv decreased and CFIp increased during occlusion. Beyond an occlusive LVEDP > 27 mmHg, Rcoll and Rperiph increased as a function of LVEDP. CONCLUSION Recruitable collaterals are reciprocally tied to LV filling pressure during occlusion. If poorly developed, they affect it via myocardial ischaemia; if well grown, LV filling pressure still increases gradually during occlusion despite the absence of ischaemia indicating transmission of collateral perfusion pressure to the LV. With low, but not high, collateral flow, resistance to collateral as well as coronary peripheral flow is related to LV filling pressure in the high range.

The association between admission systolic blood pressure and mortality in significant traumatic brain injury: A multi-centre cohort study

INTRODUCTION Low systolic blood pressure (SBP) is an important secondary insult following traumatic brain injury (TBI), but its exact relationship with outcome is not well characterised. Although a SBP of <90mmHg represents the threshold for hypotension in consensus TBI treatment guidelines, recent studies suggest redefining hypotension at higher levels. This study therefore aimed to fully characterise the association between admission SBP and mortality to further inform resuscitation endpoints. METHODS We conducted a multicentre cohort study using data from the largest European trauma registry. Consecutive adult patients with AIS head scores >2 admitted directly to specialist neuroscience centres between 2005 and July 2012 were studied. Multilevel logistic regression models were developed to examine the association between admission SBP and 30 day inpatient mortality. Models were adjusted for confounders including age, severity of injury, and to account for differential quality of hospital care. RESULTS 5057 patients were included in complete case analyses. Admission SBP demonstrated a smooth u-shaped association with outcome in a bivariate analysis, with increasing mortality at both lower and higher values, and no evidence of any threshold effect. Adjusting for confounding slightly attenuated the association between mortality and SBP at levels <120mmHg, and abolished the relationship for higher SBP values. Case-mix adjusted odds of death were 1.5 times greater at <120mmHg, doubled at <100mmHg, tripled at <90mmHg, and six times greater at SBP<70mmHg, p<0.01. CONCLUSIONS These findings indicate that TBI studies should model SBP as a continuous variable and may suggest that current TBI treatment guidelines, using a cut-off for hypotension at SBP<90mmHg, should be reconsidered.

Solar wind dynamic pressure effect on planetary wave propagation and synoptic-scale Rossby wave breaking

We provide statistical evidence of the effect of the solar wind dynamic pressure (Psw) on the northern winter and spring circulations. We find that the vertical structure of the Northern Annular Mode (NAM), the zonal mean circulation, and Eliassen-Palm (EP)-flux anomalies show a dynamically consistent pattern of downward propagation over a period of ~45 days in response to positive Psw anomalies. When the solar irradiance is high, the signature of Psw is marked by a positive NAM anomaly descending from the stratosphere to the surface during winter. When the solar irradiance is low, the Psw signal has the opposite sign, occurs in spring, and is confined to the stratosphere. The negative Psw signal in the NAM under low solar irradiance conditions is primarily governed by enhanced vertical EP-flux divergence and a warmer polar region. The winter Psw signal under high solar irradiance conditions is associated with positive anomalies of the horizontal EP-flux divergence at 55°N–75°N and negative anomalies at 25°N–45°N, which corresponds to the positive NAM anomaly. The EP-flux divergence anomalies occur ~15 days ahead of the mean-flow changes. A significant equatorward shift of synoptic-scale Rossby wave breaking (RWB) near the tropopause is detected during January–March, corresponding to increased anticyclonic RWB and a decrease in cyclonic RWB. We suggest that the barotropic instability associated with asymmetric ozone in the upper stratosphere and the baroclinic instability associated with the polar vortex in the middle and lower stratosphere play a critical role for the winter signal and its downward propagation.