Brain to blood glutamate scavenging as a novel therapeutic modality: a review.

It is well known that abnormally elevated glutamate levels in the brain are associated with secondary brain injury following acute and chronic brain insults. As such, a tight regulation of brain glutamate concentrations is of utmost importance in preventing the neurodegenerative effects of excess glutamate. There has been much effort in recent years to better understand the mechanisms by which glutamate is reduced in the brain to non-toxic concentrations, and in how to safely accelerate these mechanisms. Blood glutamate scavengers such as oxaloacetate, pyruvate, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase have been shown to reduce blood glutamate concentrations, thereby increasing the driving force of the brain to blood glutamate efflux and subsequently reducing brain glutamate levels. In the past decade, blood glutamate scavengers have gained increasing international interest, and its uses have been applied to a wide range of experimental contexts in animal models of traumatic brain injury, ischemic stroke, subarachnoid hemorrhage, epilepsy, migraine, and malignant gliomas. Although glutamate scavengers have not yet been used in humans, there is increasing evidence that their use may provide effective and exciting new therapeutic modalities. Here, we review the laboratory evidence for the use of blood glutamate scavengers. Other experimental neuroprotective treatments thought to scavenge blood glutamate, including estrogen and progesterone, beta-adrenergic activation, hypothermia, insulin and glucagon, and hemodialysis and peritoneal dialysis are also discussed. The evidence reviewed here will hopefully pave the way for future clinical trials.

The influence of aging on poststroke depression using a rat model via middle cerebral artery occlusion.

Poststroke depression (PSD) is the most frequent psychological sequela following stroke. While previous studies describe the impact of age on brain infarct volume, brain edema, and blood-brain barrier (BBB) breakdown following ischemia, the role of age on PSD has yet to be described. Here, we examine the influence of age on PSD progression in a rat model of PSD by middle cerebral artery occlusion (MCAO). One hundred forty-three rats were divided into three groups. 48 rats 20 weeks of age underwent a sham procedure, 51 rats 20 weeks of age had MCAO, and 44 rats 22-26 months of age had MCAO. Groups were further divided into two subgroups. The first subgroup was used to measure infarct lesion volume, brain edema, and BBB breakdown at 24 h. In the second subgroup at 3 weeks after MCAO, rats were subjected to a sucrose preference test, two-way shuttle avoidance task, forced swimming test, and a brain-derived neurotrophic factor (BDNF) protein level measurement. Total and striatal infarct volume, brain edema, and BBB breakdown in the striatum were increased in older rats, as compared with younger rats. While both old and young rats exhibited depressive-like behaviors on each of the behavioral tests and lower BDNF levels post-MCAO, as compared with control rats, there were no differences between old and young rats. Although older rats suffered from larger infarct volumes, increased brain edema and more BBB disruption following MCAO, the lack of behavioral differences between young and old rats suggests that there was no effect of rat age on the incidence of PSD.

The effects of estrogen and progesterone on blood glutamate levels during normal pregnancy in women.

The purpose of this study was to examine whether changes in estrogen and progesterone levels observed during normal pregnancy influence blood glutamate levels. One-hundred and sixteen pregnant women were divided into three groups based on gestational age: group 1 included women in their first trimester, group 2 included women in their second trimester, and group 3 included women in their third trimester. A single venous blood sample was collected and analyzed for concentrations of estrogen, progesterone, glutamate-pyruvate transaminase (GPT), glutamate-oxaloacetate transaminase (GOT), and glutamate. Concentrations of blood glutamate were significantly lower during the second trimester (p < 0.001) and third trimester (p < 0.001). Blood glutamate levels were inversely correlated with levels of estrogen and progesterone throughout pregnancy (p < 0.001). Levels of GOT and GPT remained stable during the course of pregnancy, apart from a moderate reduction in GPT during the third trimester. Increases in estrogen and progesterone levels during advanced stages of pregnancy were inversely correlated with maternal blood glutamate concentrations. Once a maximal blood glutamate-reducing effect was achieved, any additional estrogen and progesterone had a negligible effect on blood glutamate. This study demonstrates the glutamate-reducing effects of estrogen and progesterone, which is most likely not mediated by a GOT/GPT conversion mechanism.

Pharmacokinetics of glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase and their blood glutamate-lowering activity in naïve rats.

Traumatic brain injury (TBI) and stroke lead to elevated levels of glutamate in the brain that negatively affect the neurological outcomes in both animals and humans. Intravenous administration of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) enzymes can be used to lower the blood glutamate levels and to improve the neurological outcome following TBI and stroke. The objective of this study was to analyze the pharmacokinetics and to determine the glutamate-lowering effects of GOT and GPT enzymes in naïve rats. We determined the time course of serum GOT, GPT, and glutamate levels following a single intravenous administration of two different doses of each one of the studied enzymes. Forty-six male rats were randomly assigned into one of 5 treatment groups: saline (control), human GOT at dose 0.03 and 0.06 mg/kg and porcine GPT at dose 0.6 and 1.2 mg/kg. Blood samples were collected at baseline, 5 min, and 2, 4, 8, 12, and 24 h after the drug injection and GOT, GPT and glutamate levels were determined. The pharmacokinetics of both GOT and GPT followed one-compartment model, and both enzymes exhibited substantial glutamate-lowering effects following intravenous administration. Analysis of the pharmacokinetic data indicated that both enzymes were distributed predominantly in the blood (central circulation) and did not permeate to the peripheral organs and tissues. Several-hour delay was present between the time course of the enzyme levels and the glutamate-lowering effects (leading to clock-wise hysteresis on concentration-effect curves), apparently due to the time that is required to affect the pool of serum glutamate. We conclude that the interaction between the systemically-administered enzymes (GOT and GPT) and the glutamate takes place in the central circulation. Thus, glutamate-lowering effects of GOT and GPT apparently lead to redistribution of the excess glutamate from the brain's extracellular fluid into the blood and can reduce secondary brain injury due to glutamate neurotoxicity. The outcomes of this study regarding the pharmacokinetic and pharmacodynamic properties of the GOT and GPT enzymes will be subsequently verified in clinical studies that can lead to design of effective neuroprotective treatment strategies in patients with traumatic brain diseases and stroke.

Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats.

BACKGROUND: Decreasing blood glutamate concentrations after traumatic brain injury accelerates brain-to-blood glutamate efflux, leading to improved neurologic outcomes. The authors hypothesize that treatment with blood glutamate scavengers should reduce neuronal cell loss, whereas administration of glutamate should worsen outcomes. The authors performed histologic studies of neuronal survival in the rat hippocampus after traumatic brain injury and treatment with blood glutamate scavengers. METHODS: Traumatic brain injury was induced on anesthetized male Sprague-Dawley rats by a standardized weight drop. Intravenous treatment groups included saline (control), oxaloacetate, pyruvate, and glutamate. Neurologic outcome was assessed using a Neurological Severity Score at 1 h, and 1, 2, 7, 14, 21, 28 days. Blood glutamate was determined at baseline and 90 min. Four weeks after traumatic brain injury, a histologic analysis of surviving neurons was performed. RESULTS: Oxaloacetate and pyruvate treatment groups demonstrated increased neuronal survival (oxaloacetate 2,200 ± 37, pyruvate 2,108 ± 137 vs. control 1,978 ± 46, P < 0.001, mean ± SD). Glutamate treatment revealed decreased neuronal survival (1,715 ± 48, P < 0.001). Treatment groups demonstrated favorable neurologic outcomes at 24 and 48 h (Neurological Severity Score at 24 and 48 h: 5.5 (1-8.25), 5 (1.75-7.25), P = 0.02 and 3(1-6.5), 4 (1.75-4.5), P = 0.027, median ± corresponding interquartile range). Blood glutamate concentrations were decreased in the oxaloacetate and pyruvate treatment groups. Administration of oxaloacetate and pyruvate was not shown to have any adverse effects. CONCLUSIONS: The authors demonstrate that the blood glutamate scavengers oxaloacetate and pyruvate provide neuroprotection after traumatic brain injury, expressed both by reduced neuronal loss in the hippocampus and improved neurologic outcomes. The findings of this study may bring about new therapeutic possibilities in a variety of clinical settings.

Blood glutamate scavenging: insight into neuroprotection.

Brain insults are characterized by a multitude of complex processes, of which glutamate release plays a major role. Deleterious excess of glutamate in the brain's extracellular fluids stimulates glutamate receptors, which in turn lead to cell swelling, apoptosis, and neuronal death. These exacerbate neurological outcome. Approaches aimed at antagonizing the astrocytic and glial glutamate receptors have failed to demonstrate clinical benefit. Alternatively, eliminating excess glutamate from brain interstitial fluids by making use of the naturally occurring brain-to-blood glutamate efflux has been shown to be effective in various animal studies. This is facilitated by gradient driven transport across brain capillary endothelial glutamate transporters. Blood glutamate scavengers enhance this naturally occurring mechanism by reducing the blood glutamate concentration, thus increasing the rate at which excess glutamate is cleared. Blood glutamate scavenging is achieved by several mechanisms including: catalyzation of the enzymatic process involved in glutamate metabolism, redistribution of glutamate into tissue, and acute stress response. Regardless of the mechanism involved, decreased blood glutamate concentration is associated with improved neurological outcome. This review focuses on the physiological, mechanistic and clinical roles of blood glutamate scavenging, particularly in the context of acute and chronic CNS injury. We discuss the details of brain-to-blood glutamate efflux, auto-regulation mechanisms of blood glutamate, natural and exogenous blood glutamate scavenging systems, and redistribution of glutamate. We then propose different applied methodologies to reduce blood and brain glutamate concentrations and discuss the neuroprotective role of blood glutamate scavenging.

Pyruvate's blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke.

In previous studies, we have shown that by increasing the brain-to-blood glutamate efflux upon scavenging blood glutamate with either oxaloacetate or pyruvate, one achieves highly significant neuroprotection particularly in the context of traumatic brain injury. The current study examines, for the first time, how the blood glutamate scavenging properties of glutamate-pyruvate transaminase (GPT), alone or in combination with pyruvate, may contribute to the spectrum of its neuroprotective mechanisms and improve the outcome of rats exposed to brain ischemia, as they do after head trauma. Rats that were exposed to permanent middle cerebral artery occlusion (MCAO) and treated with intravenous 250 mg/kg pyruvate had a smaller volume of infarction and reduced brain edema, resulting in an improved neurological outcome and reduced mortality compared to control rats treated with saline. Intravenous pyruvate at the low dose of 31.3 mg/kg did not demonstrate any neuroprotection. However, when combined with 0.6 mg/kg of GPT there was a similar neuroprotection observed as seen with pyruvate at 250 mg/kg. Animals treated with 1.69 g/kg glutamate had a worse neurological outcome and a larger extent of brain edema. The decrease in mortality, infarcted brain volume and edema, as well as the improved neurological outcome following MCAO, was correlated with a decrease in blood glutamate levels. We therefore suggest that the blood glutamate scavenging activity of GPT and pyruvate contributes to the spectrum of their neuroprotective mechanisms and may serve as a new neuroprotective strategy for the treatment of ischemic stroke.

The effects of estrogen and progesterone on blood glutamate levels: evidence from changes of blood glutamate levels during the menstrual cycle in women.

The gonadal steroids estrogen and progesterone have been shown to have neuroprotective properties against various neurodegenerative conditions. Excessive concentrations of glutamate have been found to exert neurotoxic properties. We hypothesize that estrogen and progesterone provide neuroprotection by the autoregulation of blood and brain glutamate levels. Venous blood samples (10 ml) were taken from 31 men and 45 women to determine blood glutamate, estrogen, progesterone, glucose, glutamate-pyruvate transaminase (GPT), and glutamate-oxaloacetate transaminase (GOT) levels, collected on Days 1, 7, 12, and 21 of the female participants' menstrual cycle. Blood glutamate concentrations were higher in men than in women at the start of menstruation (P < 0.05). Blood glutamate levels in women decreased significantly on Days 7 (P < 0.01), 12 (P < 0.001), and 21 (P < 0.001) in comparison with blood glutamate levels on Day 1. There was a significant decrease in blood glutamate levels on Days 12 (P < 0.001) and 21 (P < 0.001) in comparison with blood glutamate levels on Day 7. Furthermore, there was an increase in blood glutamate levels on Day 21 compared with Day 12 (P < 0.05). In women, there were elevated levels of estrogen on Days 7 (P < 0.05), 12, and 21 (P < 0.001), and elevated levels of progesterone on Days 12 and 21 (P < 0.001). There were no differences between men and women with respect to blood glucose concentrations. Concentrations of GOT (P < 0.05) and GPT (P < 0.001) were significantly higher in men than in women during the entire cycle. The results of this study demonstrate that blood glutamate levels are inversely correlated to levels of plasma estrogen and progesterone.

The activation of ß2-adrenergic receptors in naïve rats causes a reduction of blood glutamate levels: relevance to stress and neuroprotection.

This study examines the effects of the activation of ß1 and ß2-adrenergic receptors on glutamate homeostasis in the blood of naïve rats. Forty five male Sprague-Dawley rats were randomly assigned into one of seven treatment groups that were treated with various ß-adrenergic receptor agonist and antagonist drugs. Blood glutamate levels were determined at t = 0, 30, 60, 90, and 120 min. The activation of ß1 and ß2-adrenergic receptors via isoproterenol hydrochloride administration produced a marked sustained decrease in blood glutamate levels by 60 min after treatment (ANOVA, t = 60, 90 min: P < 0.05, t = 120 min: P < 0.01). Pretreatment with propranolol hydrochloride (a non-selective ß-adrenergic receptor blocker) or butaxamine hydrochloride (a selective ß2-adrenergic receptor blocker) occluded the isoproterenol-mediated decrease in blood glutamate levels. Propranolol alone had no effect on blood glutamate levels. Selective ß1-adrenergic receptor blockade with metoprolol resulted in decreased blood glutamate levels (ANOVA, t = 90 min: P < 0.05, t = 120 min: P < 0.01). Butaxamine hydrochloride alone resulted in a delayed-onset increase in glutamate levels (ANOVA, t = 120 min: P < 0.05). The results suggest that the activation of ß2 receptors plays an important role in the homeostasis of glutamate in rat blood.

Distribution of radiolabeled l-glutamate and d-aspartate from blood into peripheral tissues in naive rats: significance for brain neuroprotection.

Excess l-glutamate (glutamate) levels in brain interstitial and cerebrospinal fluids (ISF and CSF, respectively) are the hallmark of several neurodegenerative conditions such as stroke, traumatic brain injury or amyotrophic lateral sclerosis. Its removal could prevent the glutamate excitotoxicity that causes long-lasting neurological deficits. As in previous studies, we have established the role of blood glutamate levels in brain neuroprotection, we have now investigated the contribution of the peripheral organs to the homeostasis of glutamate in blood. We have administered naive rats with intravenous injections of either l-[1-(14)C] Glutamic acid (l-[1-(14)C] Glu), l-[G-(3)H] Glutamic acid (l-[G-(3)H] Glu) or d-[2,3-(3)H] Aspartic acid (d-[2,3-(3)H] Asp), a non-metabolized analog of glutamate, and have followed their distribution into peripheral organs. We have observed that the decay of the radioactivity associated with l-[1-(14)C] Glu and l-[G-(3)H] Glu was faster than that associated with glutamate non-metabolized analog, d-[2,3-(3)H] Asp. l-[1-(14)C] Glu was subjected in blood to a rapid decarboxylation with the loss of (14)CO(2). The three major sequestrating organs, serving as depots for the eliminated glutamate and/or its metabolites were skeletal muscle, liver and gut, contributing together 92% or 87% of total l-[U-(14)C] Glu or d-[2,3-(3)H] Asp radioactivity capture. l-[U-(14)C] Glu and d-[2,3-(3)H] Asp showed a different organ sequestration pattern. We conclude that glutamate is rapidly eliminated from the blood into peripheral tissues, mainly in non-metabolized form. The liver plays a central role in glutamate metabolism and serves as an origin for glutamate metabolites that redistribute into skeletal muscle and gut. The findings of this study suggest now that pharmacological manipulations that reduce the liver glutamate release rate or cause a boosting of the skeletal muscle glutamate pumping rate are likely to cause brain neuroprotection.

The effect of hyperthermia on blood glutamate levels.

INTRODUCTION: Glutamate neurotoxicity is determined by the balance between glutamate release within the brain and efflux of excess glutamate from the brain. Brain-to-blood efflux of glutamate is increased by decreasing the concentration of glutamate in blood. Little is known about the effect of hyperthermia on blood glutamate concentrations, and the effectiveness of blood glutamate-decreasing mechanisms in these conditions. Although hyperthermia is hypothesized to decrease blood glutamate concentrations by activation of stress mechanisms, blunting the stress response by blocking ß-adrenergic receptors should prevent this decrease. Furthermore, during hyperthermia there should be a concurrent process of leakage of glutamate from muscle tissue into blood, resulting in a contradictory increase of blood glutamate concentrations. In this study we investigated the effects of hyperthermia on blood glutamate levels and studied the effects of the ß-adrenergic receptor antagonist propranolol on stress-induced changes in glutamate levels. We then studied the effectiveness of the blood glutamate scavenger oxaloacetate on hyperthermia-induced increases of glutamate levels. MATERIALS AND METHODS: Twenty-four rats were randomly divided into 3 groups. Rats' body temperatures were increased (by 1°C every 40 minutes) from 37°C to 42°C. The first group received 1 mL per 100 g of isotonic saline (control). The second group received 1 mL per 100 g of 1M oxaloacetate when the temperature reached 39°C. The third group received 10 mg/kg of propranolol before initiation of the warming. RESULTS: Warming the rats from 37°C to 39°C decreased the blood glutamate levels in the control group (P < 0.01) and oxaloacetate treatment group (P < 0.0001), whereas further increases in temperature from 40°C to 42°C increased the blood glutamate levels (P < 0.01 and P < 0.0001, respectively). Pretreatment with propranolol prevented the decrease in blood glutamate concentrations seen in mild hyperthermia and did not affect the increase in blood glutamate levels seen at temperatures of 41°C and 42°C (P < 0.005). DISCUSSION: The results of this study demonstrated that hyperthermia leads to decreases in glutamate levels in the blood, presumably by activation of the sympathetic nervous system. Oxaloacetate, previously reported to reduce blood glutamate levels at 37°C, was ineffective at temperatures over 40°C. Propranolol pretreatment blunted the initial decrease in blood glutamate, and thereafter had no effect when compared with control and treatment groups. Understanding the mechanisms underlying glutamate regulation in the blood during states of hyperthermia and stress has important clinical implications in treating neurodegenerative conditions.

Risk of aspiration during anesthesia in patients with congenital insensitivity to pain with anhidrosis: case reports and review of the literature.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease, characterized by episodes of unexplained fever, anhidrosis, pain insensitivity despite intact tactile perception, self-mutilating behavior, mental retardation, and autonomic nervous system (ANS) abnormalities. We present a case series of three patients with CIPA who underwent semielective orthopedic surgery under general anesthesia complicated by intraoperative regurgitation, and subsequent aspiration in two of the three cases. All three patients were nil per os (NPO) for at least 8 h prior to surgery. Two patients had their airways maintained with a laryngeal mask airway (LMA), and one patient had an endotracheal tube (ETT). The patients with an LMA suffered aspiration of gastric contents and subsequently developed hypoxic cardiac arrest. Although the patient with an ETT in situ regurgitated intraoperatively, the presence of the ETT prevented aspiration and any further potential complications. We review the perioperative complications typically observed in patients with CIPA and discuss the risks of using an LMA in these patients. We recommend that patients with CIPA always should be considered as having a "full stomach", regardless of the duration of their NPO status, due to their coexisting ANS abnormalities. Therefore, rapid-sequence induction with an ETT should be utilized for the anesthetic management in every patient with CIPA.

Secondary electron emission contrast of quantum wells in GaAs p-i-n junctions.

The secondary electron (SE) signal over a cleaved surface of GaAs p-i-n solar cells containing stacks of quantum wells (QWs) is analyzed by high-resolution scanning electron microscopy. The InGaAs QWs appear darker than the GaAsP barriers, which is attributed to the differences in electron affinity. This method is shown to be a powerful tool for profiling the conduction band minimum across junctions and interfaces with nanometer resolution. The intrinsic region is shown to be pinned to the Fermi level. Additional SE contrast mechanisms are discussed in relation to the dopant regions themselves as well as the AlGaAs window at the p-region. A novel method of in situ observation of the SE profile changes resulting from reverse biasing these structures shows that the built-in potential may be deduced. The obtained value of 0.7 eV is lower than the conventional bulk value due to surface effects.

Hemodynamic changes in visceral organs following closed head trauma in rats.

BACKGROUND: Gastrointestinal (GI) tract dysfunction is well documented following head injury. Our study sought to determine whether head injury causes an immediate impairment of the splanchnic circulation which may contribute to later GI sequelae. METHODS: Three groups of eight rats each received either no closed head trauma (CHT) (group 1) or CHT (groups 2 and 3) immediately following baseline measurements at time 0. The primary measures of interest - individual organ blood flows and cardiac output (radioactive microspheres), and individual organ and systemic vascular resistances - were determined in the control group, at 5 min after CHT in group 2, and at 15 min after CHT in group 3. RESULTS: CHT caused no significant change in portal venous inflow (flows were 2.40+/-0.36, 2.38+/-0.54, and 2.33+/-0.62 ml min(-1) 100g(-1)bw, mean+/-S.D., in groups 1, 2, and 3, respectively). Individual organ and total hepatic blood flow, cardiac index, splanchnic, portal, and total peripheral resistance, and mean arterial or portal venous pressure also did not differ significantly among groups. CONCLUSION: We found no significant changes in splanchnic circulation immediately after CHT in this rat model. Our results do not support the hypothesis that the splanchnic circulation is impaired immediately after head injury and that splanchnic blood flow impairment immediately after head injury may contribute to post-head injury GI dysfunction.

Electronic structure of methoxy-, bromo-, and nitrobenzene grafted onto Si(111).

The properties of Si(111) surfaces grafted with benzene derivatives were investigated using ultraviolet photoemission spectroscopy (UPS) and X-ray photoelectron spectroscopy (XPS). The investigated materials were nitro-, bromo-, and methoxybenzene layers (-C(6)H(4)-X, with X = NO(2), Br, O-CH(3)) deposited from diazonium salt solutions in a potentiostatic electrochemical process. The UPS spectra of the valence band region are governed by the molecular orbital density of states of the adsorbates, which is modified from the isolated state in the gas phase due to molecule-molecule and molecule-substrate interaction. Depending on the adsorbate, clearly different emission features are observed. The analysis of XPS intensities clearly proves multilayer formation for bromo- and nitrobenzene in agreement with the amount of charge transferred during the grafting process. Methoxybenzene forms only a sub-monolayer coverage. The detailed analysis of binding energy shifts of the XPS emissions for determining the band bending and the secondary electron onset in UPS spectra for determining the work function allow one to discriminate between surface dipole layers--changing the electron affinity--and band bending, affecting only the work function. Thus, complete energy band diagrams of the grafted Si(111) surfaces can be constructed. It was found that silicon surface engineering can be accomplished by the electrochemical grafting process using nitrobenzene and bromobenzene: silicon-derived interface gap states are chemically passivated, and the adsorbate-related surface dipole effects an increase of the electron affinity.

Electronic properties of Si surfaces and side reactions during electrochemical grafting of phenyl layers.

The electrochemical grafting process of 4-nitrobenzene and 4-methoxybenzene (anisole) from diazonium salt solutions has been investigated in situ by monitoring the current density, the band bending, and the nonradiative surface recombination during grafting at different potentials and different concentrations of the diazonium salt in the solution. Ex situ infrared spectroscopic ellipsometry has been used to inspect the Si surface species before and after the grafting process. The band bending decreases with either increasing concentration of diazonium salt or when the redox potential of the diazonium compound (anisole) is nearer to the competing H+/H2 couple. The surface recombination increases at more cathodic potentials if an electron donor group is present at the phenyl ring (nitrobenzene) and vice versa for the electron acceptor group (anisole). The influence of side reactions can be reduced by use of moderate concentration and moderate or strong cathodic potential, depending on the redox potential of the diazonium compound.

Ketamine improves survival in burn injury followed by sepsis in rats.

Ketamine was reported to decrease cytokine production and improve survival after Escherichia coli-induced sepsis. We examined whether ketamine decreased interleukin (IL)-6 production and improved survival after 1) burn injury or 2) burn injury combined with sepsis (E. coli) at 24 h. Ketamine (10 mg/kg) or saline was given at 1 h after burn injury (G 1, 2, 5, 6), 24 h after burn injury (G 3, 4), or at E. coli inoculation (G 7, 8). Mortality was recorded for 7 days and IL-6 was measured in serum at 6 h after burn (G 1-2), 30 h after burn (G 3-4), or 6 h after sepsis (30 h after burn) (G 5-8). Burn injury only: Ketamine given immediately (1 h) after burn injury but not 24 h after, decreased the burn-induced increase of IL-6 but did not improve survival. Burn injury + sepsis: Ketamine given immediately after burn injury did not significantly decrease the sepsis-induced increase of IL-6 or improve survival. In contrast, ketamine given immediately after sepsis significantly improved survival (46.1% versus 13.3%, P = 0.008) and decreased IL-6 production (72,640 +/- 40,990 vs 332,300 +/- 32,300 pg/mL, P = 0.008). We conclude that ketamine therapy improves survival in burn injury followed by sepsis. This beneficial effect is probably achieved through interference with the inflammatory cascade, as evidenced by attenuation of the proinflammatory marker IL-6.

Atomic force and scanning electron microscopy of atmospheric particles.

Atomic force microscopy (AFM) and scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS) have been used for both morphological and elemental mass analysis study of atmospheric particles. As part of the geometrical particle analysis, and in addition to the traditional height profile measurement of individual particles, AFM was used to measure the volume relative to the projection area for each particle separately, providing a particle shape model. The element identification was done by the EDS analysis, and the element mass content was calculated based on laboratory calibration with particles of known composition. The SEM-EDS mass measurements from two samples collected at 150 and 500 m above the surface of the Mediterranean Sea were found to be similar to mass calculations derived from the AFM volume measurements. The AFM results show that the volume of most of the aerosols that were identified as soluble marine sulfate and nitrate aerosol particles can be better estimated using cylindrical shapes than spherical or conical geometry.

Establishment of an animal model of depression contagion.

BACKGROUND: Depression is a common and important cause of morbidity, and results in a significant economic burden. Recent human studies have demonstrated that that depression is contagious, and depression in family and friends might cumulatively increase the likelihood that a person will exhibit depressive behaviors. The mechanisms underlying contagion depression are poorly understood, and there are currently no animal models for this condition. METHODS: Rats were divided into 3 groups: depression group, contagion group, and control group. After induction of depression by 5 weeks of chronic unpredictable stress, rats from the contagion group were housed with the depressed rats (1 naïve rat with 2 depressed rats) for 5 weeks. Rats were then subjected to sucrose preference, open field, and forced swim tests. RESULTS: The sucrose preference was significantly reduced in the depressed rats (p<0.01) and contagion depression rats (p<0.01). Climbing time during forced swim test was reduced in the depression and contagion depression groups (p<0.001), whereas immobility time was significantly prolonged in only the depression group (p<0.001). Rats in both the depression (p<0.05) and depression contagion group (p<0.005) had decreased total travel distance and decreased mean velocity in the open field test, whereas the time spent in the central part was significantly shorter in only the depression group (p<0.001). CONCLUSIONS: In this study, for the first time we demonstrated depression contagion in an animal model. A reliable animal model may help better understand the underlying mechanisms of contagion depression, and may allow for future investigations of the studying therapeutic modalities.

LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces brain edema and improves long-term neurological function recovery after closed head trauma in rats.

Bradykinin is an endogenous inflammatory agent that enhances vascular permeability and produces tissue edema. We investigated whether LF 16-0687 Ms, a potent nonpeptide antagonist of bradykinin type-2 (B(2)) receptor, was able to reduce brain swelling and to improve the recovery of neurological function following closed head trauma (CHT) in rats. In dose-effect studies, LF 16-0687 Ms doses of 0.75-4.5 mg/kg given 1 h after trauma significantly reduced the development of edema in the injured hemisphere by a maximum of 70%. It had no effect on the brain water content of sham-operated rats. LF 16-0687 Ms also significantly improved neurological recovery evaluated by a Neurological Severity Score (NSS) based on motor, reflex, and behavioral tests. In time-window studies LF 16-0687 Ms (2.25 mg/kg) was given 1, 2, 4, and 10 h after CHT. The extent of edema was significantly reduced when LF 16-0687 Ms was given 1 h (-45%), 2 h (-52%), and 4 h (-63%) but not 10 h (-24%) after CHT. Given at any time-point, LF 16-0687 Ms significantly improved the recovery of the NSS at 24 h. In duration of treatment studies, rats tended to recover normal neurological function over 14 days after CHT. However, time to recovery was longer in severely than in moderately injured animals, unless they were treated with LF 16-0687 Ms. This study provides further evidence that blockade of bradykinin B(2) receptors represents a potential effective approach to the treatment of focal cerebral contusions.