Pulse pressure variability is associated with unfavorable outcomes in acute ischaemic stroke patients treated with intravenous thrombolysis.

BACKGROUND AND PURPOSE: Blood pressure (BP) variability has been associated with worse neurological outcomes in acute ischaemic stroke (AIS) patients receiving treatment with intravenous thrombolysis (IVT). However, no study to date has investigated whether pulse pressure (PP) variability may be a superior indicator of the total cardiovascular risk, as measured by clinical outcomes. METHODS: Pulse pressure variability was calculated from 24-h PP measurements following tissue plasminogen activator bolus in AIS patients enrolled in the Combined Lysis of Thrombus using Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization (CLOTBUST-ER) trial. The outcomes of interest were the pre-specified efficacy and safety end-points of CLOTBUST-ER. All associations were adjusted for potential confounders in multivariable regression models. RESULTS: Data from 674 participants was analyzed. PP variability was identified as the BP parameter with the most parsimonious fit in multivariable models of all outcomes, and was independently associated (P < 0.001) with lower likelihood of both 24-h neurological improvement and 90-day independent functional outcome. PP variability was also independently related to increased odds of any intracranial bleeding (P = 0.011) and 90-day mortality (P < 0.001). Every 5-mmHg increase in the 24-h PP variability was independently associated with a 36% decrease in the likelihood of 90-day independent functional outcome (adjusted odds ratio 0.64, 95% confidence interval 0.52-0.80) and a 60% increase in the odds of 90-day mortality (adjusted odds ratio 1.60, 95% confidence interval 1.23-2.07). PP variability was not associated with symptomatic intracranial bleeding at either 24 or 36 h after IVT administration. CONCLUSIONS: Increased PP variability appears to be independently associated with adverse short-term and long-term functional outcomes of AIS patients treated with IVT.

High magnetic field Mössbauer studies of deoxymyoglobin, deoxyhemoglobin, and synthetic analogues.

Mössbauer spectra of deoxymyoglobin, deoxyhemoglobin, and the synthetic analogues, iron (II) 2-methylimidazole meso-tetraphenylporphyrin, and iron (II) 1,2-dimethylimidazole meso-tetraphenylporphyrin have been observed in high magnetic fields and over a wide range of temperature. At temperatures greater than 20 K all materials exhibit remarkably similar spectra, with anisotropic internal magnetic fields decreasing as 1/T. All have negative quadrupole interaction, and both this and the magnetic anisotropy imply that the orbital of the odd electron is prolate in the ground quintet, with little unquenched orbital angular momentum. At 4.2 K the spectra differ, suggesting different detailed structure within the quintet. In contrast to the proteins, the 2-methyl model exhibits spectra at 4.2 K which imply that the lowest spin state has high susceptibility in a single direction.

Metabolic consequences of very-low-calorie diet therapy in obese non-insulin-dependent diabetic and nondiabetic subjects.

To determine the effects of very-low-calorie diets on the metabolic abnormalities of diabetes and obesity, we have studied 10 obese, non-insulin-dependent diabetic (NIDDM) and 5 obese, nondiabetic subjects for 36 days on a metabolic ward during consumption of a liquid diet of 300 kcal/day with 30 g of protein. Rapid improvement occurred in the glycemic indices of the diabetic subjects, with mean (+/- SEM) fasting plasma glucose falling from 291 +/- 21 to 95 +/- 6 mg/dl (P less than 0.001) and total glycosylated hemoglobin from 13.1 +/- 0.7% to 8.8 +/- 0.3% (P less than 0.001) (normal reference range 5.5-8.5%). Lipid elevations were normalized with plasma triglycerides reduced to less than 100 mg/dl and total plasma cholesterol to less than 150 mg/dl in both groups. Hormonal and substrate responses were also comparable between groups with reductions in insulin and triiodothyronine and moderate elevations in blood and urinary ketoacid levels without a corresponding rise in free fatty acids. Electrolyte balance for sodium, potassium, calcium, and phosphorus was initially negative but approached equilibrium by completion of the study. Magnesium, in contrast, remained in positive balance in both groups throughout. Total nitrogen loss varied widely among all subjects, ranging from 70 to 367 g, and showed a strong positive correlation with initial lean body mass (N = 0.83, P less than 0.001) and total weight loss (N = 0.87, P less than 0.001). The nondiabetic group, which had a significantly greater initial body weight and lean body mass than the diabetic group, also had a significantly greater weight loss of 450 +/- 31 g/day compared with 308 +/- 19 g/day (P less than 0.01) in the diabetic subjects. The composition of the weight lost at completion was similar in both groups and ranged from 21.6% to 31.3% water, 3.9% to 7.8% protein, and 60.9% to 74.5% fat. The contribution of both water and protein progressively decreased and fat increased, resulting in unchanged caloric requirements during the diet. This study demonstrates that short-term treatment with a very-low-calorie diet in both obese diabetic and nondiabetic subjects results in: safe and effective weight loss associated with the normalization of elevated glucose and lipid levels, a large individual variability in total nitrogen loss determined principally by the initial lean body mass, and progressive increments in the contribution of fat to weight loss with stable caloric requirements and no evidence of a hypometabolic response.

Synergistic induction of gene 33 expression by retinoic acid and insulin.

The expression of gene 33 in rat liver and hepatoma cells is regulated by multiple hormones and other bioactive agents. Previous studies have demonstrated a 15-fold increase in gene 33 mRNA after 1 h of insulin treatment. We demonstrate in this report that retinoic acid (RA) also controls the expression of this gene. Gene 33 mRNA levels are rapidly elevated by RA, with maximal accumulation (19-fold over control) attained after just 1 h of RA treatment. The transcription rate of gene 33 was increased by RA to a maximum level 6-fold greater than control values. Studies with inhibitors of RNA synthesis demonstrated no increase in the stability of gene 33 mRNA in response to RA or insulin. In addition, a synergistic induction of both gene 33 mRNA levels and the transcription rate of gene 33 was observed when both RA and insulin were added together. In the presence of both hormones, the transcription rate was induced almost 20-fold in 30 min, followed by a 49-fold increase in mRNA levels after 1 h. Thus, gene 33 represents the first example of a gene whose transcription rate is elevated directly by both insulin and RA, and synergistically elevated by treatment with both hormones together.

Heterogeneity affecting outcome from acute stroke therapy: making reperfusion worse.

BACKGROUND: Stroke patients are heterogeneous not only with respect to etiology but also in terms of preexisting clinical conditions. Approximately one fifth of patients with acute stroke are hyperglycemic and/or have had a recent infectious or inflammatory condition. Summary of Review-- Experimental research indicates that these factors can alter and accelerate the evolution of stroke and reperfusion injury, although these effects are complex and some may have a favorable impact. Both conditions involve activation of inflammatory and reactive oxygen mechanisms. In addition, hyperglycemia has concomitant deleterious vascular and metabolic effects that worsen infarct size and encourage hemorrhagic transformation in reperfusion models. Clinical data are less extensive but in general support an adverse impact on outcome. CONCLUSIONS: After examining these data in detail, we concluded that the presence of these clinical conditions could assist in identification of those at increased risk for complications of reperfusion therapy. Furthermore, consideration of these factors may provide a rational basis for combination therapy and improve the clinical relevance of experimental stroke models.

Neuropsychological and cognitive psychophysiological substrates of impulsive aggression.

The purpose of this study was to test whether subjects who commit impulsive vs non-impulsive aggression differ on measurements of personality, neuropsychology, and cognitive psychophysiology, and whether these differences can yield information regarding the etiology of impulsive aggression. Subjects were two groups of prison inmates, distinguished by their committal of impulsive or nonimpulsive aggression, and matched noninmate controls. All inmates met DSM III-R criteria for an antisocial personality disorder but for no other disorder. Impulsiveness, anger, and peak P300 latencies did not differ between the inmate groups, but verbal symbol decoding and peak P300 amplitudes did. Impulsiveness and verbal skills were inversely correlated. Impulsiveness was inversely correlated with, and verbal skills positively correlated with P300 amplitudes. The results indicate that aggression is not homogenous, even among antisocial persons, and that impulsive aggression is related to neuropsychological and cognitive psychophysiological measures of information processing beyond those factors related to criminality alone.

Amitriptyline normalizes tetrabenazine-induced changes in cerebral microcirculation.

The cerebromicrocirculation in the tetrabenzaine (TBZ) model of depression has been found to be abnormal with respect to (1) responsiveness of cerebral blood flow to increases in arterial CO2 content and (2) the effective permeability of the blood-brain barrier to water. Development of these abnormalities temporally paralleled the behavioral disturbances and catecholamine depletion induced by TBZ. These TBZ-induced changes occurred globally throughout the brain, being apparent in the forebrain, cerebellum, and medulla-pons. Pretreatment with the antidepressant amitriptyline prevented both behavioral and physiological effects of TBZ, whereas amitriptyline administered after TBZ was less effective. The results suggest that an important action of tricyclic antidepressants may be cerebromicrocirculatory effects.

Calcium channels and nifedipine inhibition of serotonin-induced [3H]thymidine incorporation in cultured cerebral smooth muscle cells.

Cultures of smooth muscle cells were prepared from the basilar artery of adult guinea pigs. Passaged cultures (10-30 passages) that expressed serotonin receptors were studied using [3H]thymidine incorporation. When tested in quiescent medium, serotonin potently stimulated [3H]thymidine incorporation (EC50 of 31 nM) by as much as 400% at 24 h. The number of cells was not significantly increased at 24 or 48 h. At concentrations of 10(-8)-10(-5) M 5-HT, [3H]thymidine uptake was reduced 40-50% by the dihydropyridine Ca2+ channel blocker, nifedipine (1 microM). To demonstrate a possible mechanism for the sensitivity to nifedipine, Ca2+ currents were measured using the whole cell patch clamp technique. The cells expressed dihydropyridine-sensitive L-type Ca2+ channels, but not other subtypes of Ca2+ channels, as indicated by the kinetic and voltage-dependent characteristics of the current and by the stimulatory effect of Bay K 8644. The magnitude of the Ca2+ currents was related exponentially to the membrane surface area, measured as cell capacitance. These data support the association of dihydropyridine-sensitive Ca2+ channels with mitogenesis in vascular smooth muscle, and suggest an alternate mechanism of action for the beneficial effect of dihydropyridines in prophylaxis of cerebral vasospasm.

In vivo detection of superoxide anion production by the brain using a cytochrome c electrode.

A cytochrome c-coated platinized carbon electrode was utilized to detect superoxide generated by the brain during hypoxia/hypercarbia, focal ischemia, and reperfusion and following fluid percussion brain injury with and without hemorrhagic hypotension and reperfusion in the rat. All three of these forms of brain injury were associated with an increase in the superoxide signal. The cytochrome c electrode proved to be sensitive and responsive enough for minute-by-minute measurement of superoxide generation by brain tissue.

NG-nitro-L-arginine methyl ester modifies the input function measured by dynamic susceptibility contrast magnetic resonance imaging.

In rat brain dynamic susceptibility contrast magnetic resonance (MR) images, vessels visible on the same scan plane as the brain tissue were used to measure the characteristics of the input function of the MR contrast agent gadopentetate dimeglumine. MR images were acquired 30 and 60 minutes after intravenous injections of 3 mg/kg and 15 mg/kg NG-Nitro-L-arginine methyl ester (L-NAME) (n = 9). The time of arrival (TOA) and the mean transit time corrected for TOA of the input function were increased by 3 mg/kg or 15 mg/kg L-NAME. The area of the input function was increased by 15 mg/kg L-NAME. In two animals, similar modifications of the input function induced by 20 mg/kg L-NAME were reversed by infusion of sodium nitroprusside. In two other animals, MABP was increased by phenylephrine to a similar extent as in L-NAME experiments, but did not induce the same modifications of the input function, showing that the action of L-NAME on the input function was not simply caused by an effect on MABP. These results show that the input function can be significantly altered by manipulations widely used in cerebrovascular studies. These input function changes have important implications for calculation of cerebral blood flow.

Perfusion deficit parallels exacerbation of cerebral ischemia/reperfusion injury in hyperglycemic rats.

Magnetic resonance imaging (MRI) techniques were used to determine the effect of preexisting hyperglycemia on the extent of cerebral ischemia/reperfusion injury and the level of cerebral perfusion. Middle cerebral artery occlusion (MCAO) was induced by a suture insertion technique. Forty one rats were divided into hyperglycemic and normoglycemic groups with either 4 hours of continuous MCAO or 2 hours of MCAO followed by 2 hours of reperfusion. Diffusion-weighted imaging (DWI) was performed at 4 hours after MCAO to quantify the degree of injury in 6 brain regions. Relative cerebral blood flow (CBF) and cerebral blood volume (CBV) were estimated using gradient echo (GE) bolus tracking and steady-state spin echo (SE) imaging techniques, respectively. Brain injury correlated with the perfusion level measured in both SE CBV and dynamic GE CBF images. In the temporary MCAO model, mean lesion size in DWI was 118% larger and hemispheric CBV was reduced by 37% in hyperglycemic compared with normoglycemic rats. Hyperglycemia did not significantly exacerbate brain injury or CBV deficit in permanent MCAO models. We conclude that preexisting hyperglycemia increases acute postischemic MRI-measurable brain cellular injury in proportion to an associated increased microvascular ischemia.

Superoxide anion production during reperfusion is reduced by an antineutrophil antibody after prolonged cerebral ischemia.

Neutrophils may be involved in the pathophysiology of reperfusion injury following cerebral ischemia. One potential mechanism of reperfusion injury by neutrophils is through production of the superoxide anion. We hypothesized that, due to progressive endothelial damage during ischemia, neutrophil activation would be more prominent after longer periods of ischemia prior to reperfusion. Thus, neutrophils would contribute more to pathological processes such as superoxide anion formation after longer than after shorter periods of ischemia. A reversible middle cerebral artery occlusion model in rats was employed and superoxide anion concentration was measured with a cytochrome c coated electrode placed on the cortical penumbral region. Occlusion times were varied from 60 min to 2 h, and neutrophils were inhibited with an antiCD18 antibody administered prior to occlusion. Neutrophil accumulation and reduction with antibody treatment was confirmed immunohistochemically. Superoxide anion (O2*-) concentration was detected during the hours following 60 min of occlusion, and increased further with 2 h of occlusion. Treatment with the antiCD18 antibody had no effect on O2*- concentration during reperfusion in the 60-90 min occlusion groups, but O2*- concentration was significantly lower in the antiCD18 antibody treated group than in the control group during reperfusion after 120 min of ischemia. The antibody also reduced cortical neutrophil accumulation in the 120 min ischemia group. These results indicate for the first time that superoxide production by neutrophils becomes more important with longer periods of ischemia, and other quantitatively less important sources of superoxide predominate with shorter periods of ischemia. This phenomenon may explain some of the variation seen between different models of ischemia with different durations of ischemia when targeting reactive oxygen species, and supports an approach to combination therapy to extend the therapeutic window and reduce the deleterious effects of reperfusion.

Postmarketing surveillance by patient self-monitoring: preliminary data for sertraline versus fluoxetine.

BACKGROUND: There have been no published postmarketing reports comparing sertraline with another serotonin selective reuptake inhibitor (SSRI) in large-sample, parallel groups. As part of an ongoing postmarketing surveillance study, this paper presents preliminary data for a number of adverse clinical events reported by outpatients being treated with either fluoxetine or sertraline. METHOD: Using a well-validated method developed to signal possible adverse drug reactions, data were collected on 1577 fluoxetine-treated and 1209 sertraline-treated patients who filled a prescription for either of the two targeted drugs. Pharmacists gave these patients an announcement, part of which served as an entry form, that described the purpose and details of the study. Volunteers (highly selective) were requested to report during the next month via a toll-free telephone interview "any new or unusual symptoms or unexpected improvements" in their health since starting the designated medication. RESULTS: Almost 1 (31.4%) of every 3 sertraline-treated patients called at least once to report one or more adverse clinical events compared with only about 1 (19.7%) of every 5 fluoxetine-treated patients. Most of the reported adverse clinical events--but not all--are well-known adverse drug reactions that seem common to SSRIs. Adverse clinical events reported more frequently by sertraline-treated patients included urinary, sexual, psychological, neurologic, gastrointestinal, and dermatological complaints. Drug discontinuation was also reported more frequently by sertraline-treated patients. Fluoxetine-treated patients reported an increased frequency of weight gain and anger or aggression. CONCLUSION: These data indicate that many adverse reactions known to be induced by fluoxetine are being reported with even greater frequency by sertraline-treated patients. Possible interpretations of these differences are discussed.

The 21-aminosteroid U-74389G reduces cerebral superoxide anion concentration following fluid percussion injury of the brain.

We examined the effects of the 21-aminosteroid antioxidant U-74389G (16-desmethyl-tirilazad) on the concentration of extracellular superoxide anion following fluid percussion traumatic brain injury (TBI) measured by a cytochrome c-coated electrode and on local cerebral perfusion (CBFld) measured by laser Doppler flowmetry (LDF). U-74389G in a dose of 3 mg/kg reduced superoxide anion concentrations 60 min after TBI significantly but had no significant effect on CBFld. These results indicate that reduction of CBF after TBI can be dissociated from superoxide anion production. Persistent ischemia may limit neuroprotection efficacy and may contribute to divergent outcome results in clinical and animal trials using agents to modify reactive oxygen species.

Cerebromicrocirculatory defects in animal model of depression.

In the tetrabenazine (TBZ) model of depression, the cerebromicrocirculation was discovered to respond abnormally to metabolic demand as mimicked by the administration of CO2. Altered responsivity of cerebral blood flow and effective permeability of the blood--brain barrier to changes in PaCO2 were found. These physiologic defects coincided temporally with TBZ-induced depletion of central norepinephrine and dopamine and with the development of the behavioral effects of TBZ (the end points used to test the antidepressant potential of experimental drugs). Pretreatment with amitriptyline (a standard antidepressant and amine reuptake inhibitor) prevented the development of these TBZ-induced abnormalities in the cerebromicrocirculation, just as it prevented the behavioral effects.

APE/Ref-1 responses to ischemia in rat brain.

Cerebral ischemia and the aftermath of reperfusion form a hypoxic/hyperoxic sequence of events that can trigger oxidative stress response cascades in neurons of the central nervous system. After transient ischemia there is an increase in intracellular Ca2+ release, extracellular glutamate, reactive oxygen species (ROS) and nitric oxide, genotoxic events that stimulate DNA repair. Increased oxidative stress and interrupted blood flow in ischemia, like DNA repair, also deplete cellular ATP and commit neurons to apoptosis. We report that levels of the DNA repair enzyme apurinic/apyrimidinic endonuclease (APE/Ref-1) decreased significantly in the hippocampus but not other brain areas after 6 h of reperfusion following an induced ischemic insult. This specific inhibition of APE/Ref-1 expression may affect the extent of apoptosis after ischemia.

A modified method for the simultaneous determination of regional single-transit brain extraction of diffusion-limited compounds and cerebral blood flow: utilization of non-invasive measurement of transit time.

A dual-label radioisotope method to measure regional cerebral blood flow (CBF) with [14C]butanol and the single-transit brain extraction of [3H]water (Ew) was modified to permit concomittant measurement of the exit time through the cerebrovasculature of a bolus (BET) of 51chromium (51Cr)-labeled ethylenediaminetetraacetic acid (EDTA) in rodents. First, [51Cr]EDTA was injected intravenously via the femoral vein and its transit through cerebrovasculature determined by external gamma counting. The BET measurement was then used to determine the optimum time for animal sacrifice for subsequent measurement of CBF and Ew to minimize both intravascular contamination and washout of butanol and water. This procedure resulted in higher CBF at moderate hypercapnia and slightly lower Ew as a function of arterial CO2 content than previously found using a fixed interval for sacrifice.

Effect of CO2 on a brain extracellular space marker and evidence of its neuronal modulation.

Increases in inspired CO2 consistently altered the local concentration of the brain extracellular space marker alpha-naphthalene sulfonate (alpha-NS) as measured with ion-selective micropipettes in the rat thalamus. Stereotaxic injection of lidocaine in the region of the locus coeruleus attenuated this effect of CO2, and amitriptyline, a tricyclic anti-depressant and amine reuptake inhibitor, potentiated the effect. These results suggest that metabolic demand, as mimicked here by the addition of CO2, alters the fluid environment of the brain and central noradrenergic mechanisms may modulate this response.

5-HT1B and 5-HT2 serotonin binding sites in cultured Wistar-Kyoto rat aortic smooth muscle cells.

We studied [3H]serotonin [( 3H]5-HT) binding on cultured arterial smooth muscle cells from rat aorta. We found a high and low affinity binding site. Binding to the higher affinity site could be displaced by drugs in an order corresponding most closely with the 5-HT1B subtype, and high affinity [125I]iodo-cyanopindolol binding was also found. We found evidence for a 5-HT2 subtype using [3H]ketanserin binding, with similar results whether specific binding was determined using unlabelled ketanserin, methysergide or mianserin.

Acute increase in expression of growth associated protein GAP-43 following cortical ischemia in rat.

Focal cerebral ischemia creates an area of infarction that is surrounded by neuronal tissue that may respond to nearby damage by creating neurite growth. To determine if axonal sprouting occurs after infarction, antibodies to growth associated protein MW 43,000 (GAP-43), a protein expressed on axonal growth cones, were used to assess the level of GAP-43 immunoreactivity as a measure of sprouting. Cerebral ischemia was induced in spontaneously hypertensive rats by permanently occluding the distal middle cerebral artery and ipsilateral common carotid artery. After 1 week of recovery, the animals were perfused, the brains removed, processed, and optical densities of the immunoreaction were measured. The cortex surrounding the infarcted area had increased optical densities (mean +/- S.D. = 14.2% +/- 5.5) compared to the optical density values measured in similar areas in the contralateral hemisphere (mean +/- S.D. = 6.0% +/- 3.3), a 136% increase that is statistically significant, P < 0.05 Student's t-test. We hypothesize that this increase in GAP-43 reaction product is due to axonal sprouting in the cortex surrounding an area of infarction. These data, coupled with previous work examining synaptophysin levels after cortical infarction, support the hypothesis of sprouting and synaptogenesis in the cortex following cerebral infarction.