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Whether patient satisfaction scores can act as a catalyst for improving health care is highly debated. Some argue that pursuing patient satisfaction is overemphasized and potentially at odds with providing good care because it leads providers to overtest and overtreat patients and to bend to unreasonable patient demands, all to improve their ratings. Others cite studies showing that high patient satisfaction scores correlate with improved health outcomes. Ideally, assessing patient satisfaction metrics will encourage empathy, communication, trust, and shared decision making in the health care delivery process. From the patient's perspective, sharing such metrics motivates physicians to provide patient-centered care and meets their need for easily accessible information about their providers. In this article, the authors describe a seven-year initiative, which began in 2008, to change the culture of the University of Utah Health Care system to deliver a consistently exceptional patient experience. Five factors affected the health system's ability to provide such care: (1) a lack of good decision-making processes, (2) a lack of accountability, (3) the wrong attitude, (4) a lack of patient focus, and (5) mission conflict. Working groups designed initiatives at all levels of the health system to address these issues. What began as a patient satisfaction initiative evolved into a model for physician engagement, values-based employment practices, enhanced professionalism and communication, reduced variability in performance, and improved alignment of the mission and vision across hospital and faculty group practice teams.

We have locked the frequency of a 3 THz quantum cascade laser (QCL) to that of a far-infrared gas laser with a tunable microwave offset frequency. The locked QCL line shape is essentially Gaussian, with linewidths of 65 and 141 kHz at the -3 and -10 dB levels, respectively. The lock condition can be maintained indefinitely, without requiring temperature or bias current regulation of the QCL other than that provided by the lock error signal. The result demonstrates that a terahertz QCL can be frequency controlled with 1-part-in-10(8) accuracy, which is a factor of 100 better than that needed for a local oscillator in a heterodyne receiver for atmospheric and astronomic spectroscopy.

In two studies people judged the order in which two real-world events occurred. Ordering performance was better for events that were recent or widely separated in time. Ordering performance was also consistently related to predicted event memorability and to the amount of processing given to an event during encoding. Ordering performance was not consistently related to the person-typicality, pleasantness, or emotional intensity of the events, and was also not related to whether the two events judged came from the same thematic category. These results suggest that memory for event order is not entirely reconstructed from event content. We suggest that the self-concept may sometimes serve as an implicit timekeeper in autobiographical memory.

Unlabelled: Background and Purpose-Chemokines have been shown to play an important role in leukocyte and monocyte/macrophage infiltration into ischemic regions. The purpose of this study is to identify whether overexpression of the active human transforming growth factor-ss1 (ahTGF-ss1) can downregulate expression of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and intercellular adhesion molecule-1 (ICAM-1) and reduce ischemic brain injury., Methods: -Overexpression of transforming growth factor-ss1 (TGF-ss1) was achieved through adenoviral gene transfer. Five days after adenoviral transduction, the mouse underwent 30 minutes of middle cerebral artery occlusion followed by 1 to 7 days of reperfusion. TGF-ss1, MCP-1, MIP-1alpha, and ICAM-1 were detected by enzyme-linked immunosorbent assay and immunohistochemistry. Infarct areas and volumes were measured by cresyl violet staining., Results: -MCP-1 and MIP-1alpha expression is increased after middle cerebral artery occlusion, and double-labeled immunostaining revealed that MCP-1 is colocalized with neurons and astrocytes. Viral-mediated TGF-ss1 overexpression was significantly greater at measured time points, with a peak at 7 to 9 days. The expression of MCP-1 and MIP-1alpha, but not ICAM-1, was reduced in the mice overexpressing ahTGF-ss1 (P:<0.05). Furthermore, infarct volume was significantly reduced in the mice overexpressing ahTGF-ss1 (P:<0.05)., Conclusions: -This study demonstrates that MCP-1 and MIP-1alpha expressed in the ischemic region may play an important role in attracting inflammatory cells. The reduction of MCP-1 and MIP-1alpha, but not ICAM-1, in the mice overexpressing ahTGF-ss1 suggests that the neuroprotective effect of TGF-ss1 may result from the inhibition of chemokines during cerebral ischemia and reperfusion.

Objective: To quantitatively measure the temporal profiles of intercellular adhesion molecule-1 (ICAM-1) protein in mouse brain after middle cerebral artery occlusion (MCAO)., Methods: Adult male CD-1 mice received 0, 3, 6, 12, 24, 48 and 72 hour(s) of permanent MCAO with an intraluminal suture technique. The degree and the extent of occlusion were determined using a laser Doppler flowmeter. ICAM-1 positive expression in ischemic regions was determined immunohistochemically and ICAM-1 protein was quantitatively measured using immunoprecipitation and Western blot analysis., Results: After MCAO, surface cerebral blood flow (CBF) in the ischemic hemisphere decreased to 9%-15% of the baseline in each time point of 7 to 8 animals. There were no significant differences in CBF measurement during occlusion between groups. Immunohistochemistry showed that ICAM-1 positive microvascular endothelial cells were observed both in the ischemic core and in the perifocal region. There was a tendency for increasing expression of ICAM-1 positive microvascular endothelial cells from the ischemic core to the ischemic margin. Western blot analysis showed that ICAM-1 expression in the ischemic hemisphere began to increase 3 h after MCAO, peaked at 6 h to 12 h, and persisted to 72 h., Conclusions: ICAM-1 expression increases in mice with permanent MCAO because ICAM-1 can mediate leukocyte-endothelial adhesion and progression of leukocyte infiltration after permanent focal cerebral ischemia. ICAM-1 is one of the important factors participating in ischemic cerebral damage and pathogenesis of stroke.

Although both intracerebral and subdural hematomas induce brain edema, previous studies have indicated that they may have different cerebrovascular effects. Our own investigations have demonstrated that while subdural hematomas (SDH) are associated with ischemia this is not the case following intracerebral hematomas (ICH). Previous studies have demonstrated a decrease in energy-dependent transport of glutamine across the blood-brain barrier (BBB) following focal cerebral ischemia. The present study investigates this further by examining the effects of SDH, ICH, and intracerebral thrombin injections, an agent involved in ICH-induced injury, on blood to brain glutamine transport. The injection of 200 microL of blood into the subdural space induced a marked reduction in glutamine transport (Ki, influx rate constant) into the cerebral cortex at 4 and 24 h following SDH (sham, 105+/-4% of contralateral cortex; SDH 4 h, 63+/-5%, p<0.01; SDH 24 h, 47+/-12%, p<0.05). There were no significant changes in glutamine Ki in subcortical areas following SDH. Following ICH (200-microL clot); however, there were only modest decreases in glutamine Ki in subcortical areas (sham, 98+/-2% of right cortex; ICH 4 h, 91+/-5%, p<0.01; ICH 24 h, 91+/-2%, p<0.05). Intracerebral injection of thrombin (5U) had minimal effect on glutamine Ki, in subcortical areas, at 4 h and induced a modest decrease in transport at 24 h (sham, 98+/-2% of right cortex; thrombin 4 h, 98+/-2%; thrombin 24 h, 86+/-2%, p<0.05). The present studies demonstrate marked differences in the effects of ICH and SDH on BBB function.

Interleukin-1beta (IL-1beta) is expressed after cerebral ischemia and blocking its action reduces subsequent ischemic brain injury. However, the mechanisms by which IL-1beta affects ischemic brain are not understood. To investigate the role of IL- 1beta in regulation of tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) during focal cerebral ischemia, the authors studied mutant mice deficient in the IL-1 converting enzyme (ICE) gene (ICE knockout [KO] mice). Ninety-four adult male ICE KO and wild-type mice underwent 3, 6, 12, and 24 hours of permanent middle cerebral artery occlusion using the suture method. Expression of TNF-alpha and ICAM-1 protein in ischemic brain was examined using immunohistochemistry and Western blot analysis. Neither ICE KO nor wild-type mice had significant differences in CBF and body temperature measurements during the ischemic procedure. TNF-alpha expression increased in the ipsilateral hemisphere after 3 hours of occlusion, peaked at 12 hours and decreased at 24 hours of ischemia in both ICE KO and wild-type mice. ICAM-1 immunohistochemistry showed that the number of ICAM-1-positive vessels in the ischemic hemisphere was reduced in ICE KO mice (P < .05). Western blot analysis showed that ICAM-1 protein expression was significantly attenuated in the ipsilateral hemisphere in the ICE KO mice, which paralleled the immunohistochemistry results. The authors' results indicate that TNF-alpha expression is increased in both ICE KO and wild-type mice suggesting that TNF-alpha expression is not related to or upregulated by IL-1beta . ICAM-1 expression is significantly reduced in the ICE KO mice suggesting that IL-1beta plays an important role in the upregulation of adhesion molecules during focal cerebral ischemia.

Objective: Previous studies of traumatic brain injury (TBI) and hemorrhagic shock (HS) models, have shown cardiorespiratory depression in ethanol-treated animals. This study investigated the effects of ethanol (ET) on brain lactate concentrations and acidosis in a TBI/HS model., Methods: Anesthetized swine were instrumented and subjected to injury (INJ) consisting of fluid percussion TBI of 3 atm with concurrent 30 ml/kg graded hemorrhage over 30 min. Three groups were studied: Sham, INJ and INJ/ET. ET was given preinjury as a 2-g/kg i.v. bolus over 30 min, and an infusion of 0.4 g kg(-1) h(-1). Cardiorespiratory and cerebral physiologic data were monitored continuously for 150 min postinjury. Cerebral and renal blood flow was measured with colored microspheres. Brains were frozen in situ with liquid nitrogen. Lactate was measured with an enzymatic method., Results: ET levels at injury were 219+/-24 mg/dl. The INJ/ET group had increased mortality, impaired ventilation, and reduced renal blood flow. Brain (cortical) lactate levels were significantly higher and cerebral venous lactate concentrations were increased in the INJ/ET group during the postinjury period. Cerebral venous glucose was significantly higher in the INJ/ET group, and cerebral venous pH was significantly lower., Conclusion: In this TBI/HS model, ethanol-induced increases in lactate concentrations in brain tissue and cerebral venous blood are associated with respiratory depression and reduced organ blood flow., (Copyright 1999 Published by Elsevier Science B.V.)

Intracerebroventricular infusions of an amiloride analog, benzamil, reduce blood pressure in several rat models of hypertension. This effect has been attributed to an inhibition of amiloride-sensitive Na+ channels in the brain. This study examines whether intracerebroventricular benzamil would prevent the onset of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats and whether this effect correlates with an inhibition of ion transport through the known amiloride-sensitive cation channels at the blood-brain barrier. We also examine whether the effects of benzamil on blood pressure are mediated by a Na+ channel by comparing the effects of different amiloride analogs. Benzamil (0.15 and 0.5 microgram/h icv) did significantly attenuate the increase in blood pressure induced by DOCA treatment. This antihypertensive effect, however, was not associated with an alteration in a blood-brain barrier ion transport as assessed by measurements of blood-to-brain 22Na transport and cerebral spinal fluid Na+ and K+ concentrations. Indeed, intracerebroventricular infusion of dimethyl amiloride, an amiloride analog with low affinity for Na+ channels, also attenuated the increase in blood pressure induced by DOCA-salt treatment. Comparisons of the effects of benzamil, dimethyl amiloride, and 3,4-dichlorobenzamil, another amiloride analog, suggest that these antihypertensive effects are mediated by an inhibition of Na+/Ca2+ exchange in the brain.

Our previous studies have demonstrated that overexpression of recombinant human interleukin-1 receptor antagonist protein (IL-1ra) via gene transfer can reduce ischemic brain injury. However, the mechanism of action of IL-1ra in ischemia is unclear. Since interleukin-1 can up-regulate intercellular adhesion molecules in endothelium, the present study was designed to determine whether overexpression of the IL-1ra can reduce the expression of intercellular adhesion molecule-1 (ICAM-1) after ischemic injury. Normal saline or adenovirus vector (1x109 particles) encoding the human IL-1ra gene (Ad.RSVIL-1ra) or the Escherichia coli LacZ gene (Ad.RSVlacZ) was injected into the right lateral cerebral ventricle of adult CD-1 mice. After five days, permanent middle cerebral artery occlusion (MCAO) was achieved for 24 h using an intraluminal suture. Cerebral blood flow was monitored by transcranial laser Doppler flowmetry to verify the occlusion. ICAM-1 protein was quantified using Western blot analysis and localized using immunohistochemistry. After MCAO, surface blood flow in the ischemic hemisphere was decreased to 9-11% of the baseline. There were fewer ICAM-1 positive vessels in the ischemic cortex of the Ad.RSVIL-1ra transfected mice than in the Ad.RSVlacZ transfected and saline treated mice (138+/-19 vs. 249+/-25, 284+/-22, p<0.05). Western blot analysis shows that ICAM-1 protein decreased 50-60% in the Ad. RSVIL-1ra group compared to the other two groups. There were no significant differences in the numbers of positive vessels in the ischemic basal ganglia and contralateral hemisphere among the three groups. Our studies suggest that IL-1ra overexpression can down-regulate the expression of ICAM-1 in the ipsilateral cortex in ischemic mice. Interleukin-1 may play an important role in the activation of inflammatory reaction during focal cerebral ischemia by promoting leukocyte adhesion on the endothelium cells., (Copyright 1999 Elsevier Science B.V.)

Our study is to demonstrate the advantages and disadvantages of middle cerebral artery occlusion (MCAO) model in the mouse. CD-1 mice had permanent MCAO for 24 h, or temporary occlusion for either 1 h followed by 23 h of reperfusion or 2 h of occlusion with 22 h of reperfusion. The infarct volume and blood-brain barrier disruption were smaller in the 1-h/23-h temporary occlusion than in either the 24-h permanent occlusion group or the 2-h/22-h temporary occlusion group (p<0.05). Our study demonstrates that blood flow, infarct volume, and blood-brain barrier disruption remain important markers of focal cerebral ischemia., (Copyright 1999 Elsevier Science B.V.)

This study examines the effects of middle cerebral artery (MCA) occlusion in the rat on blood to brain glutamine transport, a potential marker of early endothelial cell dysfunction. It also examines whether the effects of ischemia on glutamine transport are exacerbated by hyperglycemia. In pentobarbital-anesthetized rats, 4 hours of MCA occlusion resulted in a marked decline in the influx rate constant for [14C]L-glutamine from 16.1+/-1.2 microL.g(-1).min(-1) in the contralateral hemisphere to 7.3+/-2.5 microL.g(-1).min(-1) in the ischemic core (P < 0.001). This reduction was even greater in xylazine-ketamine-anesthetized rats in which the influx decreased to 2.6+/-1.1 microL.g(-1) min(-1). This greater reduction appears related to the hyperglycemia induced by xylazine-ketamine anesthesia. Glucose injection in pentobarbital-anesthetized rats also resulted in a greater decline in [14C]L-glutamine influx in the ischemic core but had no effect on the contralateral tissue. The effects of hyperglycemia on glutamine transport in the ischemic tissue were associated with a decline in plasma volume, which may reflect either endothelial cell swelling or plugging of the microvasculature. The reduction in glutamine transport during ischemia was progressive, but even as early as 1 hour, there was a 60% and 40% decline in influx in hyperglycemic and normoglycemic rats, respectively. The fall in [14C]L-glutamine influx may reflect a dissipation of the endothelial cell [Na+] gradient. A decline in this gradient would affect many blood-brain barrier transporters with potentially deleterious effects on the ischemic brain.

Object: Traumatic brain injury (TBI) is exacerbated by hypotension and hypoventilation. Because previous studies have shown a potentiating effect of ethanol (EtOH) on TBI and hemorrhagic shock (HS), the authors investigated the effects of EtOH on the early physiological response to TBI with and without HS., Methods: Anesthetized swine, weighing approximately 20 kg each, underwent fluid-percussion TBI of 3 atm with or without 30 ml/kg hemorrhage for a period of 30 minutes. The mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure (CPP), cardiac output, cerebral venous oxygen saturation, and metabolic parameters were monitored for 3 hours postinjury. Ventilation and the response to hypercapnia were also measured. Regional cerebral blood flow and renal blood flow were measured using dye-labeled microspheres. Five groups were studied: control, TBI, TBI/EtOH, TBI/HS, and TBI/HS/EtOH. The EtOH (3.5 g) was given intragastrically 100 minutes preinjury. The TBI/HS/EtOH group demonstrated a 3-hour mortality rate of 56% and postinjury apnea requiring ventilation in 44% of animals compared with 0% in all other groups. Minute ventilation and the hypercapnic ventilatory response were significantly reduced in the postinjury period in the TBI/HS/EtOH group. The animals in this group had significantly lower CPP and cardiac output in the first 60 minutes postinjury, as well as lower renal and cerebral blood flow. Postinjury cerebral venous lactate levels were higher, and cerebral venous pH was lower in the TBI/HS/EtOH group., Conclusions: In this model of TBI, acute EtOH intoxication in the presence of HS potentiates the physiological and metabolic alterations that may contribute to secondary brain injury.

Tumor necrosis factor alpha (TNFalpha) is a pleiotrophic cytokine with diverse proinflammatory actions. Focal cerebral ischemia induces rapid and dramatic increases in TNFalpha levels within and surrounding the focus of damaged brain both in striatum and cortex. The actions of TNFalpha during cerebral ischemia may be related to the cell types which deliver and/or accept TNFalpha signals. However, the cellular sources of TNFalpha following cerebral ischemia have not been fully elucidated. The present study was designed to determine the cellular localization of TNFalpha following permanent middle cerebral artery occlusion (MCAO) in mice. As judged by immunohistochemistry, TNFalpha expression in the ischemic hemisphere was increased at 3 h following MCAO, peaked at 6 to 12 h, and decreased at 24 h. Double immunostaining for TNFalpha and neuron specific enolase (NSE) or glial fibrillary acidic protein (GFAP) showed that TNFalpha positive neurons were observed in both the ischemic core and perifocal region, while TNFalpha positive astrocytes were observed in the outer cortical layer, the corpus callosum, the molecular layer of the hippocampus, and periventricular areas. The presence of TNFalpha immunoreactivity in neurons and nerve fibers following MCAO suggests that TNFalpha expressed in ischemic neurons might be delivered via axonal transport, while TNFalpha immunoreactivity in astrocyte end-feet and ependymal cells following MCAO suggests that TNFalpha may be involved in blood-brain barrier disruption and the initiation of inflammation in the brain., (Copyright 1998 Elsevier Science B.V.)

It has been demonstrated that administration of an interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain injury; however, the detrimental mechanism initiated by interleukin-1 (IL-1) in ischemic brain injury is unclear. In this study, we used mice that were transfected to overexpress human IL-1ra to elucidate the role of IL-1 in the activation of the inflammatory response after middle cerebral artery occlusion (MCAO). Myeloperoxidase (MPO) activity and immunohistostaining were used as a marker of polymorphonuclear leukocytes (PMNL) infiltration. Adenoviral vector (1 x 10(9) particles) was administered by injection into the right lateral ventricle in mice. Five days later, MCAO was performed on the mice using a suture technique. Permanent MCAO was achieved for 24 hours in the Ad.RSVIL-1ra-transfected. Ad.RSVlacZ-transfected, and saline (control) mice. Myeloperoxidase activity was quantified in each region and localization of MPO was determined by immunohistochemistry. After 2 hours of MCAO, the surface cerebral blood flow was reduced to 13.5% +/- 3.4%, 10.75% +/- 2.6%, and 10.9% +/- 2.6% of baseline in the ischemic hemisphere in Ad.RSVIL-1ra-transfected, Ad.RSVlacZ-transfected, and saline-treated mice, respectively. The MPO activity in the ischemic hemisphere in the Ad.RSVlacZ group was similar to that in the saline control group (cortex: 0.40 +/- 0.22 versus 0.33 +/- 0.11; basal ganglia: 0.46 +/- 0.23 versus 0.49 +/- 0.17; P > 0.05); however, it was significantly reduced in the Ad.RSVIL-1ra group (cortex: 0.18 +/- 0.07; basal ganglia: 0.26 +/- 0.15; P < 0.05). Myeloperoxidase immunohistochemistry showed that the massive accumulation of MPO-positive cells in the ischemic cortex, striatum, and corpus callosum regions was greatly attenuated in Ad.RSVIL-1ra-transfected mice. Our results indicate that Ad.RSVIL-1ra-transfected mice provide a useful tool to study the mechanism of action of IL-1. The MPO activity assay and immunostaining after 24 hours of focal ischemia were significantly reduced in IL-1ra gene-transfected mice, suggesting that IL-1 may play an important role in the activation of inflammatory cells during focal cerebral ischemia.

Background and Purpose: Evidence suggests that cerebral edema following intracerebral hemorrhage (i.c.h.) results from a mass effect in combination with neurotoxic injury from clot-derived substrates such as thrombin. Thrombolytics can compete for thrombin inhibitors endogenous to the brain. This study examines the effect of intracerebral infusion of thrombolytics, tissue plasminogen activator (tPA), and urokinase (uPA), individually and in combination with thrombin., Methods: Various 100 microL solutions were stereotactically infused into the right basal ganglia of adult male rats. Animals were euthanized 24 hours later, and brain sections were taken for measurement of water, sodium, and potassium content., Results: Regardless of dose, when infused independently tPA (2 micrograms) and uPA (2000 and 5000 Plough units) failed to produce any significant tissue edema compared with vehicle control tissues. However, when either thrombolytic was infused concomitantly with thrombin (1 or 5 U), brain water, sodium, and potassium content all demonstrated a potentiation of thrombin-induced brain injury (P < 0.05). In addition, animal deaths were significantly greater than expected in animals receiving a combination of tPA (2 micrograms) and thrombin (5 U) compared with either drug alone (P < 0.001)., Conclusions: This study indicates that brain edema caused by thrombin can be greatly amplified by the presence of plasminogen activators, perhaps because the latter compete for naturally occurring thrombin inhibitors. In the context of ICH, our results suggest that the use of tPA or uPA to lyse clotted blood in brain parenchyma may promote edema formation in surrounding tissue.

Objective: Our purpose was to evaluate the mechanisms of cocaine's effect on both spontaneous and agonist-induced contractility of pregnant human myometrium., Study Design: Myometrium was obtained from 42 women at term who were undergoing cesarean section. Myometrial strips were suspended in contraction baths and isometric contractions were measured. Tissue was exposed to various combinations of cocaine, prazosin, desipramine, benzoylecgonine, and procaine. Spontaneous contractility and the contractile responses to increasing concentrations of methoxamine and oxytocin were measured and compared., Results: Cocaine increased spontaneous myometrial contractility by more than threefold. Prazosin, an alpha-adrenergic antagonist, blocked this effect only for the first 35 minutes of exposure. The cumulative concentration-response to the alpha-adrenergic agonist methoxamine was increased by cocaine in terms of both sensitivity and maximal response. The maximal response to oxytocin, but not the sensitivity, was increased by cocaine by an effect that could not be blocked by prazosin., Conclusion: Cocaine augments spontaneous and agonist-induced contractility of pregnant human myometrium by mechanisms that appear to be both alpha-adrenergic and nonadrenergic in nature.

Initial studies examining intraparenchymal injection of recombinant viral vectors in rodent brain have demonstrated a limited region of gene transfer. We examined, independently, different infusion parameters to determine if the volume of cells transduced acutely could be increased. Varying the rate of infusion from 0.3 to 3 microliters/min at constant time and virus dose did not improve the volume of brain transduced, with the lowest rate of infusion demonstrating the least amount of gene transfer. However, transduction volume did increase with increasing particle concentrations of virus, although the improvements were modest from 3 to 9 x 10(9) total particles infused. Infusion of virus under conditions of hypertonicity resulted in modest improvements in the final transduced volume. These studies suggest that most changes in infusion parameters will have small effects on the initial transduction volume in rodent brain.

A variety of recent studies suggest a role for both inflammatory cytokines such as interleukin-1 beta (IL-1 beta), and apoptosis in ischemic brain injury. Because IL-1 beta converting enzyme (ICE) is required for the conversion of proIL-1 beta to its biologically active form, and has homology with proteins that regulate apoptosis in invertebrates, we studied the effect of cerebral ischemia on brain injury in mutant mice deficient in the ICE gene (ICE knockout [KO] mice). Focal cerebral ischemia, produced by occlusion of the middle cerebral artery, resulted in brain edema (increased water and sodium content) at 4 hours and a histologically defined brain lesion at 24 hours. Both of these markers of brain injury were significantly reduced in the ICE KO mice as compared to wild-type C57BL/6 mice. Regional cerebral blood flow, determined using the flow tracer, N-isopropyl [methyl 1,3-(14)C] p-iodoamphetamine (14C-IMP), was similar in the two strains of mice, indicating that the reduced brain injury in the KO mice was not a result of a lesser degree of ischemia. These data show that ICE contributes to the development of ischemic brain damage, and that it plays a role at an early time in the pathologic process. Although the mechanism of this effect is uncertain, our results suggest that pharmacologic inhibition of ICE may be a useful treatment for stroke.

Hyperglycemia generally enhances cerebral ischemic injury. Most attention on a mechanism has focused on the adverse effect of increased lactate production (acidosis) leading to neuronal injury. The effects of hyperglycemia on another possible primary target, the cerebral microvasculature, is examined in this study. Focal cerebral ischemia was achieved by thread occlusion of the middle cerebral artery (MCA). Preischemic hyperglycemia was induced by intraperitoneal administration of 50% of D-glucose solution. In contrast to normoglycemic controls, glucose-injected rats showed a well demarcated pale infarct after 2 or 4 hours of ischemia reflecting a reduction in cerebral plasma volume (CPV) to 73 +/- 9 and 55 +/- 6% of contralateral by 2 and 4 hours respectively. Cerebral blood flow (CBF) measured by laser-Doppler flowmetry indicated that after the initial decline in CBF with MCA occlusion, hyperglycemia led to a further progressive reduction during ischemia. Blood-brain barrier transport measured by permeability surface area (PS) product for glutamine was reduced in both normoglycemic and hyperglycemic rats. However, the decline was greater in the hyperglycemic rats. Hyperglycemia induces progressive cerebrovascular changes and affects blood-brain barrier transport during focal cerebral ischemia. These changes may contribute to the adverse effects of hyperglycemia in stroke.

A diary methodology was used to assess factors related to temporal dating and cued recall of real-world events. In one diary, participants kept a record of unique personal autobiographical events. In a second diary, participants recorded unique events from the life of a friend or relation. At the time each event was recorded, participants rated the event's pleasantness, person typicality, and degree of initial mental involvement in the event. At the end of the academic quarter, participants provided a recall rating, a rehearsal rating, a date estimate, and a report of the strategy used to estimate the date for each event. Results of regression analyses indicated that both self-events and other-events were characterized by superior memory for person-atypical events. Furthermore, there was a positivity bias in recall for self-events, but there was a negativity bias in recall for other-events. Mediational analyses indicated that the self-event positivity bias was due to enhanced mental involvement when the events occurred, whereas the other-event negativity bias was due to subsequent event rehearsal. The date estimation results indicated that self-event dating was more accurate and evinced less telescoping than other-event dating. Furthermore, the accuracy of date estimates was substantially mediated by event memory. However, mediational differences between self-events and other-events did not emerge. The theoretical implications of these results are discussed.

To examine the mechanisms involved in cerebrospinal fluid (CSF) K+ homeostasis, lateral ventricle choroid plexuses were isolated from rats fed low, normal or high K+ diets for 2 weeks. Potassium (86Rb) influx and efflux were then examined in vitro. Dietary hypo- and hyperkalemia (2.8 +/- 0.1 and 6.8 +/- 0.3 mM) did not affect the efflux rate constant for 86Rb or the influx rate constant in the absence of inhibitors. However, the ouabain-sensitive portion of influx was only 1.9 +/- 0.5 microl/g per min in plexuses from hypokalemic rats compared to 4.5 +/- 0.5 microl/g/min in controls (P < 0.001). This change in Na+/K+-ATPase activity was reflected in an increasing amount (Western blot) of the alpha1 and beta1 subunits of this pump with increasing plasma K+ concentration (P < 0.05) whereas the beta2 subunit was unaffected. The other known choroid plexus K+ uptake mechanism, bumetanide-sensitive K+ cotransport, was unaffected by dietary K+ manipulation. In normo- and hyperkalemic rats, the sum of the ouabain- and bumetanide-sensitive fluxes could account for all of 86Rb uptake. However, in hypokalemic rats a major component (40%) of uptake could not be accounted for by either mechanism. This unidentified mechanism may be a basolateral uptake mechanism involved in increasing K+ transport from blood to CSF during hypokalemia.

It has been reported that middle cerebral artery occlusion in rats causes overexpression of interleukin-1, and that administration of the interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain injury. The aim of the present study is to determine whether a recombinant adenovirus vector carrying human interleukin-1 receptor antagonist cDNA (Ad.RSVIL-1ra) could be used to overexpress IL-1ra in mouse brain and to evaluate its effect on brain edema formation and infarction after permanent focal ischemia in mice. Ad.RSVIL-1ra, control adenovirus containing the lacZ gene (Ad.RSVlacZ), or saline was injected into the right cerebral ventricle in mice. Brain IL-1ra concentrations were measured 1 to 13 days later. On the fifth day after virus injection, the middle cerebral artery was occluded for 24 h. Brain water content was determined and a histological technique was used to measure the infarction size. Overexpression of human IL-1ra protein in whole brain was confirmed by immunoassay in the Ad.RSVIL-1ra injected mice. It began on the first day, peaked at 5-7 days, and was sustained for 13 days. Brain edema and cerebral infarct volume were significantly reduced following 24 h of permanent middle cerebral artery occlusion in mice transfected with Ad.RSVIL-1ra compared to Ad.RSVlacZ or saline 5 days earlier. These studies demonstrate that adenoviral vectors can be used to deliver genes to small animals such as mice and also suggest the feasibility of gene therapy for stroke and other neurological diseases. Overexpression of human IL-1ra attenuated ischemic brain injury, suggesting that IL-1 may play an important role in cerebral ischemia.

Background and Purpose: A well-demarcated infarct was observed after 4 hours of rat middle cerebral artery (MCA) occlusion with xylazine/ketamine but not pentobarbital or isoflurane anesthesia. This study examined whether this reflected vascular changes and, because xylazine induces hyperglycemia, whether glucose could cause similar vascular effects in cerebral ischemia., Methods: To examine the effects of anesthetics, rats were anesthetized for thread occlusion of the MCA with either xylazine/ketamine, pentobarbital, or isoflurane. To evaluate the effects of glycemia, acute hyperglycemia was induced by glucose injection. In both experiments, cerebral plasma volume (CPV) was determined using 3H-inulin after 4 hours of permanent occlusion, and cerebral blood flow was measured using [14C]iodoantipyrine following 2 hours of reperfusion after 2 or 4 hours of occlusion. The presence of cerebral hemorrhage after reperfusion was checked macroscopically and infarct volume with 2,3,5-triphenyltetrazolium staining., Results: The ischemic CPV was about 50% of the contralateral values with xylazine/ketamine but not with the other anesthetics. On reperfusion, ischemic cerebral blood flow with xylazine/ketamine anesthesia was approximately half that with pentobarbital. Use of xylazine/ketamine also resulted in more frequent hemorrhagic infarcts and a larger infarct volume. Induced hyperglycemia resulted in a CPV decrease in the ischemic compared with nonischemic tissue (4.0 +/- 0.5 versus 7.4 +/- 0.2 microL/g; P < .001). Hyperglycemia also caused poor reperfusion and increased the occurrence of hemorrhagic infarction (hyperglycemia, 15 of 20; normoglycemia, 1 of 11; P < .01)., Conclusions: Hyperglycemia induces marked cerebrovascular changes, both during ischemia and during reperfusion, that may exacerbate tissue damage. Change in CPV during ischemia may be a useful clinical indicator in predicting poor hemodynamic recovery and occurrence of hemorrhagic infarction after reperfusion therapy.

This study examines whether during bilateral carotid artery occlusion in Fischer 344 rats, hyperglycemia induces cerebrovascular changes that enhance brain edema formation. Preischemic hyperglycemia was induced by intraperitoneal administration of D-glucose solution. Laser-Doppler flowmetry, indicated that after the initial decline in blood flow with carotid occlusion (36 +/- 4% of preischemic), hyperglycemic but not control rats showed a further progressive decrease to 19 +/- 2% of preischemic at 120 minutes (p < 0.001). Brain water content was significantly higher in hypercompared to normoglycemic rats after both 2 hours of permanent occlusion (3.86 +/- 0.05 vs. 3.73 +/- 0.03 g/g dry wt.; p < 0.05) and 2 hours of temporary occlusion followed by 1 hour of reperfusion (4.01 +/- 0.08 vs. 3.71 +/- 0.03 g/g dry wt.; p < 0.05). The difference in brain edema formation between normo- and hyperglycemic rats appears to primarily reflect the effects of hyperglycemia on CBF. Cerebral plasma volume (CPV) 2 hours after occlusion was also reduced in hyper-compared to normoglycemic rats (3.9 +/- 0.9 and 7.2 +/- 0.1 microliters/g; p < 0.01). Thus, hyperglycemia in a model of global ischemia induces a reduction in CPV and progressive decline in CBF. In this model, the decline in CBF is of sufficient magnitude to enhance brain injury as evidenced by edema formation.

The Cl-/HCO3- exchanger (AE2 isoform) and the Na+/K(+)-ATPase at the choroid plexus are both thought to be involved in CSF secretion. However, both transport mechanisms are also postulated to have a role in CSF ion homeostasis raising questions as to which parameters control the expression of these transporters? Northern blots have been used to assess AE2 mRNA levels in rats subjected to alterations in blood pH or blood osmolality (a factor affecting CSF secretion). Six hours of alkalosis induced a 40% increase in AE2 mRNA (p < 0.01), suggesting that alterations in the expression of this transporter play a role in CSF pH homeostasis. In contrast, changes in osmolality did not affect AE2 mRNA. Western blots of Na+/K(+)-ATPase subunits were also examined to determine whether hypo and hyperkalemia affect protein levels of this transporter. There was a positive correlation between the plasma K+ concentration and both alpha 1- and beta 1 subunit protein levels suggesting a role for this transporter in CSF K+ homeostasis. As changes in plasma K+ and pH affect choroid plexus ion transporters but do not appear to alter CSF production, these results suggest the presence of compensatory mechanisms. Understanding of such mechanisms may facilitate therapeutic control of CSF production.

During the past several years, it has become increasingly apparent that interleukin-1 (IL-1), particularly IL-1 beta plays an important role in brain injury during ischemia. Studies from various laboratories have shown that IL-1 beta mRNA and IL-1 beta protein are synthesized early in ischemia and that the injection of IL-1 beta into ischemic brain enhances edema formation. The most direct evidence that IL-1 beta contributes to ischemic injury, however, is the demonstration that infarct volume in focal ischemia is reduced following intraventricular injection of an endogenous interleukin-1 receptor antagonist (IL-1ra), or after IL-1ra is overexpressed in brain using an adenoviral vector to transfer IL-1ra cDNA to brain cells. Ischemic injury is also reduced in mice that fail to produce IL-1 beta because of an abnormal interleukin-1 beta converting enzyme gene (ICE knockout mice). At the present time, it is nuclear how IL-1 beta causes brain injury, but several possible mechanisms include 1) stimulation of an inflammatory response through the activation of glia or the induction of other cytokines and/or endothelial adhesion molecules and 2) release of free radicals through stimulation of arachidonic acid metabolism and/or nitric oxide synthase activity.

Previous work from this laboratory has shown that injection of thrombin into rat basal ganglia causes brain edema. This study investigates the effect on rat brain of thrombin-soaked gelatin sponge (used for intraoperative hemostasis in clinical situations) at a concentration similar to that used in humans. Three models were developed to evaluate this effect. In the first model, a gelatin sponge soaked with vehicle or thrombin (100 U/cm3) was placed on the intact pia of the right frontal lobe in rats without cortical lesions. In the second model, frontal cortex was excised (3 mm3) and the exposed brain was cauterized with electrocoagulation. Gelatin sponge was soaked with vehicle or thrombin (1000, 100, 10, or 1 U/cm3) and placed in the lesion site. In the third model, hirudin, a specific thrombin antagonist, was added to the thrombin-soaked gelatin sponge and placed in a similar cortical lesion to determine if the observed effects were specific to thrombin. The dose-response range for thrombin was determined qualitatively by magnetic resonance (MR) imaging and quantitatively by brain edema formation 24 hours after exposure. We found no edema in the cortically intact rats. The rats given cortical lesions developed significant edema when subjected to 1000, 100, and 10 U/cm3 thrombin as seen on MR imaging and at 100 and 10 U/cm3 thrombin as revealed by wet/dry weight and ion studies of brain tissue. Topical hirudin prevented thrombin-induced edema. It is concluded that thrombin-soaked gelatin sponges cause or enhance significant brain edema in rats at concentrations typically used for human neurosurgery.

The mechanism of unidirectional transport of sodium from blood to brain in pentobarbital-anesthetized rats was examined using in situ perfusion. Sodium transport followed Michaelis-Menten saturation kinetics with a Vmax of 50.1 nmol/g/min and a Km of 17.7 mM in the left frontal cortex. The kinetic analysis indicated that, at a physiologic sodium concentration, approximately 26% of sodium transport at the blood-brain barrier (BBB) was carrier mediated. Dimethylamiloride (25 microM), an inhibitor of Na+/H+ exchange, reduced sodium transport by 28%, whereas phenamil (25 microM), a sodium channel inhibitor, reduced the transfer constant for sodium by 22%. Bumetanide (250 microM) and hydrochlorothiazide (1.5 mM), inhibitors of Na(+)-K(+)-2Cl-/NaCl symport, were ineffective in reducing blood to brain sodium transport. Acetazolamide (0.25 mM), an inhibitor of carbonic anhydrase, did not change sodium transport at the BBB. Finally, a perfusate pH of 7.0 or 7.8 or a perfusate PCO2 of 86 mm Hg failed to change sodium transport. These results indicate that 50% of transcellular transport of sodium from blood to brain occurs through Na+/H+ exchange and a sodium channel in the luminal membrane of the BBB. We propose that the sodium transport systems at the luminal membrane of the BBB, in conjunction with Cl-/HCO3- exchange, lead to net NaCl secretion and obligate water transport into the brain.

As summarized in Fig. 2, nearly all aspects of brain microvascular endothelial cell function may be affected by ischemia. These alterations not only interfere with BBB functions which are critical for protection of the brain, but they may also lead to the production of substances that are directly toxic to the brain. Thus, the cerebrovascular endothelial cell appears to be both a target and participant in the processes that produce damage in ischemic brain.

The coagulation cascade has a potential role in brain edema formation due to intracerebral hemorrhage. In this study blood and other solutions were injected stereotactically into the right basal ganglia in rats. Twenty-four hours following injection, brain water and ion contents were measured to determine the amount of brain edema. Intracerebral blood resulted in an increase in brain water content. The amount of brain edema surrounding the intracerebral hematoma was reduced by a thrombin inhibitor N alpha-(2-Naphthalenesulfonylglycyl)-4-amidino-DL-phenylalaninep iperidide, (alpha-NAPAP) infused into the hematoma after the clot had been allowed to solidify. The inhibitor did not alter the actual size of the clot mass. An artificial clot composed of fibrinogen, thrombin, and styrene microspheres also produced brain edema. A fibrin clot led to edema formation even in the absence of mass effect provided by the microspheres. The single component responsible for production of brain edema in all these models was thrombin. The edema was formed in response to a fibrinogen-independent pathway. These results indicate that the coagulation cascade is involved in brain edema that develops adjacent to an intracerebral hematoma.

The mechanism by which intracerebral hemorrhage leads to the formation of brain edema is unknown. This study assesses the components of blood to determine if any are toxic to surrounding brain. Various solutions were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; brain edema and ion contents were measured. Whole blood caused an increase in brain water content and ion changes consistent with brain edema. Concentrated blood cells, serum from clotted blood, and plasma from unclotted blood all failed to provoke edema formation when infused directly into the brain. On the other hand, activation of the coagulation cascade by adding prothrombinase to plasma did produce brain edema. The edema response to whole blood could be prevented by adding a specific thrombin inhibitor, hirudin, to the injected blood. This study indicates that thrombin plays an important role in edema formation from an intracerebral blood clot.

Purified thrombin from an exogenous source is a hemostatic agent commonly used in neurosurgical procedures. The toxicity of thrombin in the brain, however, has not been examined. This study was performed to assess the effect of thrombin on brain parenchyma, using the formation of brain edema as an indicator of injury. Ten microliters of test solution was infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later, and the extent of brain edema and ion content were measured. Concentrations of human thrombin as low as 1 U/microliter resulted in a significant increase in brain water content. Rats receiving 10 U/microliters had a mortality rate of 33% compared to no mortality in the groups receiving smaller doses. Thrombin-induced brain edema was inhibited by a specific and potent thrombin inhibitor, hirudin. A medical grade of bovine thrombin commonly used in surgery also caused brain edema when injected at a concentration of 2 U/microliters. Edema formation was prevented by another highly specific thrombin inhibitor, N alpha-(2-Naphthalenesulfonylglycyl)-4-DL-phenylalaninepiperidid e (alpha-NAPAP). Thrombin-induced brain edema was accompanied by increases in brain sodium and chloride contents and a decrease in brain potassium content. Changes in brain ions were inhibited by both hirudin and alpha-NAPAP, corresponding to the inhibition of brain water accumulation. This study shows that thrombin causes brain edema when infused into the brain at concentrations as low as 1 U/microliter, an amount within the range of concentrations used for topical hemostasis in neurosurgery.

1. The potassium permeability of the blood-brain barrier (BBB) was determined in anaesthetized rats aged between 21 days gestation and adult using 86Rb+ as a marker for potassium. 2. The brain influx rate constant for 86Rb+ was high in fetal cortex at 21 days gestation (42.5 +/- 4.3 microliters g-1 min-1) but had decreased markedly by just after birth (12.2 +/- 0.6 microliters g-1 min-1). There was a further, gradual, postnatal decline to 7.0 +/- 0.3 microliters g-1 min-1 by 50 days after birth. 3. Developmental changes in passive BBB permeability were examined over the same age range using 14[C]urea. These studies showed similar developmental changes in influx rate to those found for 86Rb+. Specifically, a marked perinatal decline followed by a more gradual postnatal fall. Thus, the changes in potassium permeability probably reflect a decrease in the BBB paracellular leak during development. 4. The changes in BBB permeability coincide with changes in the rate of brain growth and the associated rate of brain potassium accumulation. As the potassium permeability properties of the adult BBB would provide insufficient potassium influx to meet the requirement associated with fetal brain growth, it is suggested that need for potassium may be the reason for the greater BBB permeability early in development.

Little is known about blood to brain taurine transport despite substantial evidence suggesting a role of taurine in brain volume regulation during osmotic stress or conditions inducing cell swelling, such as ischemia. We have made measurements of the taurine influx rate constant (K1) with [3H]taurine in three conditions: raised plasma taurine concentrations induced by infusion with 50 mM taurine (10 microliters/100 g/min); osmotic stress induced by i.p. injections of 1.5 M NaCl (2 ml/100 g) or distilled water (10 ml/100 g); and 4 h of middle cerebral artery occlusion (MCAo). In rats with MCAo, additional determinations were made of tissue water and taurine contents, and blood-brain barrier passive permeability with [3H]alpha-aminoisobutyric acid. Taurine infusion increased plasma taurine from 110 +/- 63 microM (SD) to 407 +/- 63 (p < 0.001) and decreased taurine K1 at the blood-brain barrier by 70% (p < 0.001), signifying saturable uptake that maintained unidirectional influx constant. Similarly, although hypo- and hyperosmolality increased and decreased plasma taurine concentration, respectively, a reciprocal relationship between K1 and plasma taurine in these experiments ensured that unidirectional fluxes of taurine into brain were unchanged by osmotic stress. During MCAo, the taurine K1 was reduced 80% in the ipsilateral ischemic tissue compared with the contralateral nonischemic tissue (p < 0.001). This decline may be due to a release of taurine into the brain circulation, because there was a concomitant loss of tissue taurine of 7.4 +/- 2.4 mmol/g dry weight (p < 0.05). Alternately, if taurine uptake is sodium dependent, the decline might reflect a disruption of the endothelial sodium gradient.

Adenoviruses have been proposed as potential vectors for gene therapy in the central nervous system, but there are no reports of their use in the treatment of a brain disease. Because central administration of interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain damage, we determined whether a recombinant adenovirus vector carrying the human IL-1ra cDNA (Ad.RSVIL-1ra) could be used to ameliorate brain injury in permanent focal ischemia. Groups of six rats received intraventricular injections of Ad.RSVIL-1ra or a control adenovirus containing the Escherichia coli beta-galactosidase gene (Ad.RSVlacZ). Histochemical staining for beta-galactosidase 5 days after virus injection indicated that transgene expression was confined primarily to the cells lining the ventricle. The concentrations of IL-1ra injected animals, achieving levels of 9.1 +/- 3.3 ng/g in brain and 23.7 +/- 22.5 ng/ml in CSF. In these animals, cerebral infarct volume resulting from 24 h of permanent middle cerebral artery occlusion was reduced 64%. These studies demonstrate that adenoviral vectors can be used to deliver genes that attenuate brain injury.

Background and Purpose: Zinc protoporphyrin (ZnPP) has multiple actions. It is an interleukin-1 antagonist as well as a hemeoxygenase inhibitor. Interleukin-1 is produced in ischemic brain and probably contributes to ischemic injury, although the role of heme oxygenase during ischemia is unknown. Whether ZnPP treatment is more effective before or after ischemia, as well as whether it is more protective in permanent or temporary cerebral ischemia, is also unknown. Therefore, we investigated the effect of ZnPP on infarction size and edema in a rodent model of temporary and permanent focal cerebral ischemia., Methods: Two groups of adult male Sprague-Dawley rats were pretreated with either 50 mg/kg ZnPP IP or saline and subjected to permanent middle cerebral artery occlusion 30 minutes later. Four additional groups of animals were subjected to 2 hours of temporary middle cerebral artery occlusion followed by 22 hours of reperfusion. Two of these groups were pretreated 30 minutes before middle cerebral artery occlusion with either 50 mg/kg ZnPP IP or saline. The other groups received ZnPP at either 2 or 4 hours after middle cerebral artery occlusion. Regional cerebral blood flow in the ischemic cortex was monitored with laser Doppler flowmetry. Cerebral infarct size and brain water were measured 24 hours after the onset of either form of ischemia., Results: Regional cerebral blood flow after occlusion was approximately 13% to 20% of baseline after either permanent or temporary ischemia. ZnPP had no effect on regional cerebral blood flow, infarct size, or edema formation in permanent ischemia. In contrast, pretreatment significantly reduced infarct size (17.2 +/- 6.6% in controls versus 6.2 +/- 2.9% in pretreated rats) and edema formation (center zone, 4.00 +/- 0.71% water in controls versus 1.18 +/- 0.26% water in pretreated rats) in the model of temporary ischemia, but treatment after occlusion had no effect., Conclusions: ZnPP treatment protected the brain when administered early in the temporary ischemia model.

Direct intracerebral injection of recombinant adenoviral vectors within the brain parenchyma or the ventricular system results in a limited volume of distribution of virus, as demonstrated by transgene expression. Global delivery to the central nervous system may increase the use of these vectors but only if the viral vectors can cross the blood-brain barrier and result in transduction of the underlying cells. This short-term study examines whether osmotic disruption with mannitol can result in sufficient opening of the vascular endothelium to allow for passage of replication-defective adenovirus containing the Escherichia coli beta-galactosidase gene (lacZ). Virus was injected into the carotid artery of rats after blood-brain barrier disruption with intracarotid hypertonic mannitol, and the animals were killed and analyzed after 4 days. Histochemical analysis and electron microscopy confirmed expression of the E. coli lacZ gene in the pericapillary astrocytes of the ipsilateral cerebral cortex and deep grey matter. Furthermore, the extent of gene transfer and expression correlated with the degree of barrier opening, as measured by Evans blue staining. Transgene expression was not seen in control animals that received intracarotid saline before recombinant virus injection. These data demonstrate, for the first time, that blood-brain barrier disruption can allow for the delivery of functional viral vectors to the central nervous system.

The delivery of large neutral amino acids (LNAAs) to brain across the blood-brain barrier (BBB) is mediated by the L-type neutral amino acid transporter present in the membranes of the brain capillary endothelial cell. In experimental animals, the L-system transporter is saturated under normal conditions, and therefore an elevation in the plasma concentration of one LNAA will reduce brain uptake of others. In this study, we used positron emission tomography (PET) to determine the effect of elevated plasma phenylalanine concentrations on the uptake of an artificial neutral amino acid, [11C]-aminocyclohexanecarboxylate ([11C]ACHC), in human brain. PET scans were performed on six normal male subjects after an overnight fast and again 60 min after oral administration of 100 mg/kg of phenylalanine. The plasma phenylalanine concentration increased by an average of 11-fold between the first and second scans. This increase produced a reduction in [11C]ACHC uptake in all brain regions but not in scalp. The mean +/- SD influx rate constant for whole brain decreased after phenylalanine ingestion from 0.036 +/- 0.002 to 0.019 +/- 0.004 ml/g/min. Kinetic analysis of the effect of plasma phenylalanine concentration on the rate of [11C]ACHC uptake is compatible with a model of competitive inhibition so that large increases in the concentration of one LNAA in plasma will reduce the brain uptake of other LNAAs across the human BBB.

Brain and CSF potassium concentrations are well regulated during acute and chronic alterations of plasma potassium. In a previous study, we have shown that during chronic perturbations, regulation is achieved by appropriate adaptation of potassium influx, but that the degree of such adaptation during acute perturbations is much less. To elucidate further potential regulatory mechanisms, rats were rendered acutely or chronically hyper- or hypokalemic (range 2.7-7.6 mM). Measurements were made of brain and CSF water and ion contents to examine whether regulation occurred by modulation of K+ uptake into parenchymal cells. Furthermore, the permeability-surface area products (PSs) of 22Na+ were determined, because changes in K+ efflux fia Na+,K(+)-ATPase on the brain-facing side of the blood-brain barrier might be reflected in modified Na+ permeability. Brain and CSF K+ concentrations and Na PS were all independent of chronic changes in plasma K+ and acute hypokalemia, suggesting that neither modulation of parenchymal K+ uptake nor K+ efflux via the Na+,K(+)-ATPase is involved in extracellular K+ regulation in these conditions. In contrast, Na PSs were increased by 40% (p < 0.05) in acute hyperkalemia. This was accompanied by a slight loss of tissue K+ and water from the intracellular space. These results suggest that increased potassium influx in acute hyperkalemia is compensated by stimulation of K+ efflux via Na+,K(+)-ATPase. A slight degree of overstimulation, as indicated by a net loss of tissue K+, leads us to hypothesize that other factors, apart from the kinetic characteristics of Na+,K(+)-ATPase, may regulate this enzyme at the blood-brain barrier.