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A comparative experimental analysis of intensity of nitric oxide (NO) production and the copper content in the tissues of hippocampus of male Wistar rats after modeling of hemorrhagic stroke and brain injury was conducted using EPR spectroscopy. Modeling of hemorrhagic stroke was carried out by microinjection of 500 nl of autologous blood into the brain to a depth of 5.0 mm (hippocampus) on the left side. Brain injury was performed by removing a piece of nerve tissue from 5.0 mm depth on the left side of hippocampus. It was registered a significant decrease in the NO content in hippocampus by 36 ± 17% on the 3rd day after modeling of hemorrhagic stroke together with decrease by an average of 24 ± 14% of the copper content. There were no significant changes in the NO level in hippocampus found neither on the 3rd day nor on the 7th day after brain injury modeling. There was also no change in copper content. Thus, it was experimentally demonstrated that modeling of brain injury, in contrast to hypoxia induced by hemorrhagic stroke, was not accompanied with significant changes in NO production in hippocampus of rat.

Results of analysis of nitric oxide and copper content in rat liver and hippocampus after brain ischemia modeling are provided. The studies are carried out using the electron paramagnetic resonance spectroscopy method with spin traps. It was shown that, the day after brain ischemia modeling, nitric oxide content in hippocampus decreases on average by 50% and a tendency toward its decrease was observed in liver tissues. Two days after brain ischemia modeling, nitric oxide content in the brain recovered and a significant increase by 46% against control indices was observed in the liver. On the second day of the postischemic period, the copper content, which is associated with superoxide dismutase content, increased on average by 2.5-fold in the liver. No significant changes in copper content was found in the hippocampus.

A comparative experimental analysis by EPR spectroscopy of the intensity of nitric oxide (NO) production and the content of the copper in the tissues of olfactory bulb of the brain of male Wistar rats were performed after modeling of ischemic stroke and treatment with immediate intranasal injection of mesenchymal stem cells (MSCs). Brain ischemia was simulated by ligation at the level of bifurcation of the common carotid arteries. It was found a significant reduction of NO content in the olfactory bulb of the brain of rats on the 1st and 2nd days after modeling of ischemia. The level of NO production was also reduced on the 1st and 2nd days after ischemia with MSCs’ administration as compared to intact animals. It was not found the significant difference of the NO content in rats after ischemia with MSCs’ administration relative to ischemic rats. The copper content in the olfactory bulb of the rat, which corresponds to the level of superoxide dismutase 1 and 3, tended to increase after modeling ischemia and remained for 2 days. The MSCs’ administration was accompanied by a significant increase in copper content on the 1st day after modeling of ischemia and by decrease of its content on 2nd day after ischemia. The experiments showed that MSCs’ administration did not affect the intensity of NO production on the 1st and 2nd days after the modeling of brain ischemia, but was accompanied by an increase in the antioxidant protection of the nervous tissue 1 day after ischemia.

It was shown by electron paramagnetic resonance (EPR) spectroscopy that one day after bilateral occlusion of the common carotid arteries (to simulate ischemia) in Wistar rats (group 1, n = 15) under ketamine-xylazine-acepromazine anesthesia (55.6, 5.5, 1.1 mg/kg, respectively, intraperitoneally), the content of nitric monoxide (NO) in the olfactory bulbs decreased, and recovered after two days. A similar trend was observed in Wistar rats (group 2, n = 15), which, simultaneously with ischemia modeling, were implanted intranasally with mesenchymal stem cells (MSCs). An intact group of rats (group 3, n = 15) was kept in the usual conditions of the vivarium and did not undergo surgical interventions. The content of copper in the olfactory bulbs of rats (for assessing the activity of superoxide dismutases 1 and 3) after ischemia modeling (group 1) tended to increase and maintain the increase for two days of observation. Intranasal administration of MSCs during the ischemia modeling was accompanied by a more significant increase in copper content on the first day after brain ischemia modeling, but after two days, a tendency towards restoration of the initial copper level was noted.

Electron paramagnetic resonance (EPR) was used as a method to record nitric oxide (NO) production in the tissues of the brain, heart and liver of healthy rats, and rats after modeling of ischemic stroke. Direct measurement of the dynamics of NO production by EPR spectroscopy in our experiments showed that after the emergence of signs of ischemic stroke, 5 h after the start of ischemia, the content of NO in the hippocampus decreased two- to threefold and this decrease was maintained at 24 and 72 h. Deserving special attention is the data demonstrating that there is a greater decrease of NO production in the tissues of the heart and liver than in the brain. Consequently, the change in intensity of NO production in the modeling of ischemic events in the brain has a systemic, not a local character.

Deep body temperature of 57 male Wistar rats was measured in response to systemic (i.v. or i.p.) injection of Escherichia coli lipopolysaccharide (LPS). Animals were preliminarily (4 weeks before the experiment) treated with microinjections of the toxic dose of glutamate receptors agonists or vehicle into solitary tract nucleus or caudal part of ventrolateral medulla. Microinjections of the glutamate receptors agonists provoked a local destruction of brain tissue, which was accompanied by the significant transformation (amplification or attenuation) of temperature response to the systemic injection of 3 μg/kg E. coli LPS. Animals treated with vehicle did not demonstrate significant changes in their response to LPS. Obtained data testify that impairment of central nervous structure involved in the regulation and maintenance of deep body temperature is accompanied by atypical development of E. coli LPS-induced fever.

Dry immersion is an effective and useful model for research in physiology and physiopathology. The focus of this study was to provide integrative insight into renal, endocrine, circulatory, autonomic and metabolic effects of dry immersion. We assessed if the principal changes were restored within 24 h of recovery, and determined which changes were mainly associated with immersion-induced orthostatic intolerance. Five-day dry immersion without countermeasures, and with ad libitum water intake, standardized diet and a permitted short daily rise was performed in a relatively large sample for this experiment type (14 healthy young men). Reduction of total body water derived mostly from extracellular compartment, and stabilized rapidly at the new operating point. Decrease in plasma volume was estimated at 20% - 25%. Five-day immersion was sufficient to impair metabolism with a decrease in glucose tolerance and hypercholesterolemia, but was not associated with pronounced autonomic changes. Five-day immersion induced marked cardiovascular impairment. Immediately after immersion, over half of the subjects were unable to accomplish the 20-min 70° tilt; during tilt, heart rate and total peripheral resistance were increased, and stroke volume was decreased. However, 24 hours of normal physical activity appeared sufficient to reverse orthostatic tolerance and all signs of cardiovascular impairment, and to restitute plasma volume and extracellular fluid volume. Similarly, metabolic impairment was restored. In our study, the major factor responsible for orthostatic intolerance appeared to be hypovolemia. The absence of pronounced autonomic dysfunction might be explained by relatively short duration of dry immersion and daily short-time orthostatic stimulation.

Immersion is a useful tool for studying fluid-volume homeostasis. Natriuretic peptides play a vital role in renal, humoral, and cardiovascular regulation under changing environmental conditions. We hypothesized that dry immersion would rapidly induce a new steady state for water and sodium metabolism, and that serum NT-proBNP levels, a proxy measure for brain natriuretic peptide (BNP), would decrease during long-term dry immersion and increase during recovery. Eight healthy young men were studied before, during, and after 7 days of dry immersion. Body weight, water balance, and plasma volume changes were evaluated. Plasma and serum samples were analyzed for active renin, NT-proBNP, aldosterone, electrolytes, osmolality, total protein, and creatinine. Urine samples were analyzed to determine levels of electrolytes, osmolality, creatinine, and free cortisol. A stand test was performed before and after dry immersion to evaluate cardiovascular deconditioning. Long-term dry immersion induced acute changes in water and sodium homeostasis on day 1, followed by a new steady state. Plasma volume decreased significantly during dry immersion. The serum levels of NT-proBNP increased significantly in recovery (10 ± 3 ng/L before dry immersion vs. 26 ± 5 ng/L on the fourth recovery day). Heart rate in the standing position was significantly greater after immersion. Results suggest that chronic dry immersion rapidly induced a new level of water-electrolyte homeostasis. The increase in NT-proBNP levels during the recovery period may be related to greater cardiac work and might reflect the degree of cardiovascular deconditioning.

Lipopolysaccharide (LPS)-induced systemic inflammation is accompanied by either hypothermia (prevails when the ambient temperature (Ta) is subneutral) or fever (prevails when Ta is neutral or higher). Because platelet-activating factor (PAF) is a proximal mediator of LPS inflammation, it should mediate both thermoregulatory responses to LPS. That PAF possesses hypothermic activity and mediates LPS-induced hypothermia is known. We asked whether PAF possesses pyrogenic activity (Expt 1) and mediates LPS fever (Expt 2). The study was conducted in Long-Evans rats implanted with jugular catheters. A complex with bovine serum albumin (BSA) was infused as a physiologically relevant form of PAF; free (aggregated) PAF was used as a control. In Expt 1, either form of PAF caused hypothermia when infused (83 pmol kg-1 min-1, 60 min, i.v.) at a subneutral Ta of 20 degrees C, but the response to the PAF-BSA complex (-4.5 +/- 0.5 degrees C, nadir) was ~4 times larger than that to free PAF. At a neutral Ta of 30 degrees C, both forms caused fever preceded by tail skin vasoconstriction, but the febrile response to PAF-BSA (1.0 +/- 0.1 degrees C, peak) was2 times higher than that to free PAF. Both the hypothermic (at 20 degrees C) and febrile (at 30 degrees C) responses to PAF-BSA started when the total amount of PAF infused was extremely small,830 pmol kg-1. In Expt 2 (conducted at 30 degrees C), the PAF receptor antagonist BN 52021 (29 micromol kg-1, i.v.) had no thermal effect of itself. However, it strongly (~2 times) attenuated the febrile response to PAF (5 nmol kg-1, i.v.), implying that this response involves the PAF receptor and is not due to a detergent-like effect of PAF on cell membranes. BN 52021 (but not its vehicle) was similarly effective in attenuating LPS (10 microg kg-1, i.v.) fever. It is concluded that PAF is a highly potent endogenous pyrogenic substance and a mediator of LPS fever.

BACKGROUND AND OBJECTIVE: A decreased resistance to infection and impairments of immunity are common in obese humans and in rodents with hereditary obesity. Since brown fat thermogenesis is also suppressed in obese rodents, we hypothesized that obesity leads to a decreased febrile responsiveness. METHODS: We compared the fever responses to intravenous E. coli lipopolysaccharide (10 µg/kg) between Zucker fa/fa (obese due to a defective leptin receptor) and Fa/? (lean) rats and between Otsuka Long–Evans Tokushima Fatty (OLETF; obese due to the lacking cholecystokinin-A receptor) and Long-Evans Tokushima Otsuka (lean) rats. Obesity of Zucker fa/fa and OLETF rats was verified by increased body mass and fat content, hypertriglyceridemia and hypercholesterolemia. RESULTS: Neither fa/fa nor OLETF animals exhibited a decreased febrile responsiveness; if anything, their fevers tended to be higher than those in their lean counterparts. CONCLUSION: Obesity per se does not lead to antipyresis. International Journal of Obesity (2001) 25, 586–589

In rats, fevers induced by moderate-to-high doses of intravenous lipopolysaccharide consist of three phases (phases 1, 2 and 3) with body temperature peaks at approximately 1, 2, and 5 h postinjection, respectively. In this study, the effects of bilateral truncal subdiaphragmatic vagotomy and intraperitoneal capsaicin desensitization on febrile phases 1-3 were assessed in adult Wistar rats. Surgical vagotomy was performed approximately 30 d before the experiment; this procedure interrupts both afferent and efferent vagal fibers. Capsaicin was administered intraperitoneally in two consecutive injections (2 and 3 mg/kg, 3 h apart) 1 week prior to the experiment; this procedure desensitizes afferent fibers, primarily within the abdominal cavity, and does not lead to the known thermal effects of systemic capsaicin desensitization. At a neutral ambient temperature, the rats were given Escherichia coli lipopolysaccharide (10 microg/kg) through a preimplanted jugular catheter, and their colonic temperature wes measured by thermocouples for 7 h. The control rats exhibited the typical triphasic febrile responses. Confirming our earlier studies, subdiaphragmatic vagotomy did not affect phases 1 and 2; it did, however, result in a 2.5-fold reduction of phase 3. Capsaicin desensitization modified the febrile response differently: phases 2 and 3 were unaffected, but phase 1 disappeared. We suggest that neural afferent fibers (nonvagal but perhaps vagal as well) play an important role in the early febrile response (phase 1) by transducing peripheral pyrogenic signals to the brain. We also suggest that vagal efferent fibers are likely to participate in the later febrile response (phase 3) via an unknown mechanism.

This paper disproves the common belief that all doses of lipopolysaccharide (LPS) that are commonly referred to as biphasic fever inducing (≥2 μg/kg) cause truly biphasic responses. A catheter was implanted into the right jugular vein of several strains of adult male rats, and the animals were habituated to the experimental conditions. At an ambient temperature of 30.0°C, loosely restrained animals were injected with a 10 μg/kg dose of LPS (various preparations), and their colonic (Tc) and tail skin temperatures were monitored (from ≥1 h before to ≥7 h after the injection). The results are presented as time graphs and phase-plane plots; in the latter case the rate of change of Tc is plotted against Tc. In experiment 1 the intravenous injection of LPS (from Escherichia coli 0111:B4, phenol extract) into the rats (Bkl:Wistar) induced a triphasic febrile response, as is obvious from time graphs of Tc (3 peaks), time graphs of effector activity (3 waves of tail skin vasoconstriction), and phase-plane plots (3 complete loops); the injection of saline (control) induced no Tc changes. We analyzed whether the triphasic pattern was due to some peculiarities of the experimental design, i.e., the pyrogen preparation used ( experiment 2) or the rat strain tested ( experiment 3) or whether this pattern reflects a more general law. In experiment 2 we used the same (phenol) preparation of different LPS (from Shigella flexneri 1A and Salmonella typhosa) and a different preparation (TCA extract) of the same LPS ( E. coli). Regardless of the LPS used, rats of the Bkl:Wistar strain responded to the 10 μg/kg dose with the triphasic fever. In experiment 3, rats of other strains [Bkl:Sprague-Dawley and Sim:(LE)fBR(Black-hooded)] were tested. Again, all animals responded to the 10 μg/kg dose of E. coli LPS (phenol extract) with the triphasic fever. Because all fevers caused by four different LPS preparations in three rat strains were triphasic, the triphasic pattern is likely to constitute an intrinsic characteristic of the febrile response.

Subdiaphragmatically vagotomized rats cannot mount a febrile response to pyrogens and are believed to have severe thermoregulatory deficiencies. We addressed the issue of thermoeffector competence of vagotomized rats by asking three questions. In Expt. 1 we asked, can vagotomized rats readily recruit tail skin vasoconstriction in the course of a moderate cold exposure? In Expt. 2 the question was, can brown adipose tissue (BAT) thermogenesis readily be activated in vagotomized rats (e.g., in response to a tail pinch)? In Expt. 3, we investigated the question: can vagotomized rats elevate their body temperature in response to ephedrine (a drug of high hyperthermizing potential) to the same extent as sham-operated controls? Rats were vagotomized or sham operated and implanted with a catheter into the jugular vein and a thermocouple into the interscapular BAT. To prevent the common complications of vagotomy, special perioperative care was given. During experiments, colonic, tail skin, and BAT temperatures (Tc, Tsk, and TBAT, respectively) were measured. The vagotomized animals were well nourished and had a body mass (325 +/- 6 g) similar to that of the controls (338 +/- 6 g). In Expt. 1, in response to external cooling (15 degrees C, 1 h), the vagotomized (n = 30) and sham-operated (n = 31) rats recruited tail skin vasoconstriction at close values of both Tc (37.84 +/- 0.08 and 37.97 +/- 0.07 degrees C) and Tsk (33.16 +/- 0.17 and 33.18 +/- 0.18 degrees C, respectively). In Expt. 2, tail pinch-associated stress in vagotomized rats resulted in a sharp rise in the TBAT-Tc gradient by 0.3-1.0 degree C. In Expt. 3, ephedrine administered intravenously (whether in a 5 or 35 mg/kg dose) evoked similar hyperthermic responses in the vagotomized and sham-operated rats: a moderate (approximately 2.5 degrees C) Tc rise in the low dose and a "supramaximal" (approximately 5.0 degrees C) rise in the high dose. In sum, the answer to all three questions asked is yes. Vagotomized rats, at least when well nourished, exhibit no signs of thermoeffector deficiency. It is, therefore, not effector incompetence but rather vagal deafferentation per se that can explain the febrile irresponsiveness of vagotomized rats.

Experimentally, systemic inflammation induced by a bolus intravenous injection of lipopolysaccharide (LPS) may be accompanied by three different thermoregulatory responses: monophasic fever (the typical response to low doses of LPS), biphasic fever (medium doses), and hypothermia (high doses). In our recent study [Romanovsky, A. A., V. A. Kulchitsky, C. T. Simons, N. Sugimoto, and M. Szekely. Am. J. Physiol. (Regulatory Integrative Comp. Physiol.). In press], monophasic fever did not occur in subdiaphragmatically vagotomized rats. In the present work, we asked whether vagotomy affects the two other types of thermoregulatory response. Adult Wistar rats were vagotomized (or sham operated) and had an intravenous catheter implanted. On day 28 postvagotomy, the thermal responses to the intravenous injection of Escherichia coli LPS (0, 1, 10, 100, or 1,000 micrograms/kg) were tested in either a neutral (30 degrees C) or slightly cool (25 degrees C) environment. Three major results were obtained. 1) In the sham-operated rats, the 1 microgram/kg dose of LPS caused at 30 degrees C a monophasic fever with a maximal colonic temperature (Tc) rise of approximately 0.6 degree C; this response was abated (no Tc changes) in the vagotomized rats. 2) At 30 degrees C, all responses to higher doses of LPS (10-1,000 micrograms/kg) were represented by biphasic fevers (the higher the dose, the less pronounced the first and the more pronounced the second phase was); none of these biphasic fevers was altered in the vagotomized animals. 3) In response to the 1,000 micrograms/kg dose at 25 degrees C, hypothermia occurred: Tc changed by -0.5 +/- 0.1 degree C (nadir); this hypothermia was exaggerated (-1.1 +/- 0.1 degrees C) in the vagotomized rats. It is concluded that vagal afferentation may be important in the mediation of the response to minor amounts of circulating LPS, whereas the response to larger amounts is brought about mostly (if not exclusively) by nonvagal mechanisms. This difference may be explained by the dose-dependent mechanisms of the processing of exogenous pyrogens. Vagotomized animals also appear to be more sensitive to the hypothermizing action of LPS in a cool environment; the mechanisms of this phenomenon remain speculative.

In acute experiments on nembutal–urethan-anaesthetized rats, a slow infusion of subseptic dose of lipopolysaccharide (LPS) Escherichia coli (1 mg/ml) via the right jugular vein immediately led to bradycardia and extrasystoles. Preliminary administration of 20 mg/kg N (G)-nitro- l -arginine methyl ester ( l -NAME) or 30 mg/kg aminoguanidine hydrochloride prevented the LPS-induced extrasystoles but did not affect the pattern of bradycardia. We conclude that nitric oxide (NO)-ergic mechanisms are involved in provoking electrical instability of the heart in conditions of endotoxemia.

Intraperitoneal capsaicin desensitizes sensory fibers traveling within both the vagus and splanchnic nerves. Because capsaicin desensitization blocks the first phase of lipopolysaccharide (LPS) fever, whereas surgical vagotomy does not, splanchnic mediation of the first phase was proposed. However, all phases of the febrile response of splanchnicotomized rats to intravenous LPS (10 microg/kg) were similar to those of sham-operated controls. Hence, the splanchnic nerve is likely uninvolved in LPS fever.

The study was designed to test whether intact vagal innervation of the liver is required for the formation of tolerance to lipopolysaccharide (LPS). Wistar rats were subjected to either denervation of the liver (transection of the hepatic and both celiac branches of the abdominal vagus) or sham surgery. Two weeks later, each rat had an osmotic pump implanted subcutaneously. The pump was filled with either a suspension of Escherichia coli LPS (18 mg/ml) in saline or saline alone. Via a catheter, the pump delivered its content into the right jugular vein at a rate of approximately 0.72 microl/kg/h (approximately 13 microg/kg/h of LPS) over 28 d. On day 25 of the infusion, each animal had another catheter implanted into the left jugular vein. Three days later, each rat was injected with a lethal bolus dose of LPS (15 mg/kg) and had its colonic temperature recorded. The saline-infused sham-operated rats responded to the bolus injection of LPS with hypothermia followed by a fever (mean response magnitude 1.0+/-0.2 degrees C); 91% of the animals died within 24 h. The LPS-primed shams developed marked tolerance: When challenged with a lethal dose of LPS, they exhibited a significantly smaller thermal response (magnitude 0.5 +/- 0.2 degrees C) and none died. No group of the vagotomized animals, whether LPS- or saline-primed, became tolerant: Both groups exhibited similar hypothermic responses to the bolus LPS injection and a substantial mortality rate (40 and 100%, respectively). The study shows that prolonged infusion of low doses of LPS leads to the formation of tolerance and that vagal denervation of the liver by hepato-celiac vagotomy suppresses this process. The mechanisms of vagal control of the formation of LPS tolerance remain speculative.

The repeatedly observed attenuation of fever in vagotomized rats has been accepted as evidence of an essential role of vagal afferents in the transduction of pyrogenic signals from the periphery to the brain. If, however, the general condition of a vagotomized animal is poor (the usual case) and accompanied by malnutrition and body mass loss (common complications of vagotomy), the febrile responsiveness can be suppressed not because of the lack of vagal afferentation, but rather secondarily to a malnutrition-associated thermogenic incompetence. In the present study, we addressed this dilemma. Male Wistar rats were subjected to subdiaphragmatic vagotomy (or sham surgery) and, 24 days later, catheterized in the jugular vein. Postsurgically, the rats were closely watched and fed highly palatable food. Their febrile responsiveness [colonic (Tc) and tail skin (Tsk) temperature responses] to Escherichia coli lipopolysaccharide (LPS: 1 microgram/kg i.v.) was tested on day 27 postvagotomy. To verify the completeness of vagotomy, each rat was food deprived for 24 h and then euthanized; its stomach's evacuatory function was assessed by weighing the organ. One month postsurgery, both food consumption and body mass of the vagotomized rats (33 +/- 2 g/day and 313 +/- 4 g, respectively) were similar to the control values (30 +/- 1 g/day and 315 +/- 8 g). In the sham rats, LPS induced a monophasic Tc rise of 0.5 +/- 0.3 degree C at 70 min postinjection (peak), preceded by a fall in Tsk. Neither this Tsk fall (tail skin vasoconstriction) nor the resultant fever occurred in the vagotomized rats; at 70 min, Tc change was -0.1 +/-0.1 degree C. The gastric mass (4.1 +/- 0.5 g in the vagotomized vs. 1.8 +/- 0.1 g in sham rats) indicated the effectiveness of vagotomy. In sum, although the vagotomy-associated malnutrition was successfully prevented with special perioperative care, the vagotomized animals still did not respond to LPS with fever. Malnutrition is, therefore, unlikely to constitute the main reason of the febrile irresponsiveness of vagotomized rats.

In acute experiments on nembutal-urethan-anesthetized rats, structures selectively sensitive to capsaicin were found near the ventral surface of the medulla at the exit of hypoglossal nerve roots. Microinjection of 5-50 nl 0.01% capsaicin to the rostral region of the capsaicin-sensitive area mostly activated respiration, arterial pressure and heart rate (HR) while that to the caudal region inhibited arterial pressure and HR. In chronic experiments on rats, injection of 25 nl 1% capsaicin to the caudal capsaicin-sensitive area led to a decrease in arterial pressure by 35-45% and in HR by 10-15% within a week after operation. Arterial pressure and HR virtually reached the control level and the rostral and caudal ventral medulla showed asymmetric distribution of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-positive cells by the end of the 2nd week. It is suggested that nitric oxide may be involved in the mechanisms of neurochemical rearrangements in the brainstem after application of capsaicin to the caudal ventrolateral medulla (CVLM).

s / Neuropeptides 40 (2006) 417–445 443 are known to correlate negatively with body mass index (BMI) so that ghrelin is elevated in anorexia nervosa and decreased in obesity. In patients with cancer cachexia, it has been postulated that lack of appetite and weight loss, despite elevated ghrelin levels, results from partial ghrelin resistance. Exogenous ghrelin administered to these patients has been shown to increase caloric intake by 31%. In this study, we have shown that increased endogenous release of ghrelin from neuroendocrine tumors (NETs) can overcome the partial ghrelin resistance seen in cancer cachexia. Methods: The study was conducted as a single-center, prospective trial enrolling 35 patients with NETs. Total ghrelin levels and chromogranin A (CgA) values were measured and analyzed for differences by t test (p < 0.05). Subgroups examined included patients with and without hepatic metastases, carcinoid versus pancreatic NETs, and patients with and without hypergastrinemia due either to prolonged proton pump inhibitor use or due to Zollinger-Ellison Syndrome (ZES). Results: Mean total ghrelin levels in patients with NET and hepatic metastases (589 pg/ml) were significantly elevated compared to the group of NET patients without hepatic metastases (411 pg/ml). The former had a mean BMI of 27.2 compared to a mean of 26.3 for the latter. These higher ghrelin levels correlated with higher serum chromogranin A levels. Mean total ghrelin in patients with hypergastrinemia due to prolonged proton pump inhibitor therapy (591 pg/ml) differed significantly from untreated patients (418 pg/ml). No significant differences in ghrelin levels were seen in patients with carcinoid tumors compared to those with pancreatic neuroendocrine tumors nor between patients with Zollinger-Ellison syndrome versus those without. All patients with neuroendocrine tumors had elevated levels of ghrelin compared to the standard reference range. Conclusions: We report that in all subgroups analyzed, patients with NETs had levels of ghrelin that positively correlated with BMI suggesting that any partial ghrelin resistance may be overcome with increased endogenous ghrelin. This data supports the possibility that ghrelin is co-released from NETs and exerts an orexigenic effect in these patients, helping to maintain weight preservation despite widely disseminated disease. doi:10.1016/j.npep.2006.09.044 P-8: INVOLVEMENT OF PROTEOGLYCANCONTAINING CELLS AND/OR THE PROTEOGLYCAN EXTRACELLULAR MATRIX IN SYNAPTIC TRANSMISSION Yu.S. Garkun , A.A. Denisov , P.G. Molchanov , N.V. Yakubovich , V.A. Kulchitsky ; a Institute of Physiology, National Academy of Sciences, 28 Akademicheskaya Str., 220072, Minsk, Belarus; b Belarus State University, 4 Nezavisemosty Ave., 220050, Minsk, Belarus In many respects cell-to-cell communications are determined by interaction between cells and extracellular matrix. We attempted to change the functional state of the extracellular matrix by applying chondroitin sulfate to test the hypothesis that proteoglycans can influence synaptic transmission in brain slices by transforming extracellular matrix. Experimental series were performed on 400 lm-thick hippocampal slices from 3–4-week old rats. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSPs) in the CA1 area were recorded under electrical stimulation of the Schaffer collaterals in a series of 48 hippocampal slices taken from 16 young rats under perfusion with 0.001– 1.0% chondroitin sulfate. Beginning at 60s after application of 0.01% chondroitin sulfate, an increase in the amplitude of the fEPSPs in response to both paired pulse stimuli was induced and persisted until 90s. Following this, the fEPSPs in response to both pulses declined rapidly over 60s, to an extent whereby fEPSPs were almost abolished. The initial facilitation of fEPSPs and PSs amplitudes following chondroitin sulfate may result from either an increase in net excitatory post-synaptic current or an increase in post-synaptic impedance. Similarly, the subsequent impairment of fEPSPs and PSs amplitude in the period 90 to 150s after chondroitin application presumably reflects a reduction in excitatory post-synaptic current or a large fall in postsynaptic impedance. All these processes can be initiated by structural shifts in perineuronal nets including changes of a configuration of active zones and receptor ratio. Thus, proteoglycans may influence interneuronal communications in the CA1 region of the hippocampus. doi:10.1016/j.npep.2006.09.045 P-9: VASOACTIVE INTESTINAL PEPTIDE MODULATES PLASMACYTOID DENDRITIC CELL FUNCTION BY ALTERATION OF THE IMMUNE PHENOTYPE AND INHIBITION OF IFNA SECRETION D. Fabricius , M. Sue O’Dorisio , Sue Blackwell , Bernd Jahrsdoerfer ; a Department of Pediatrics, University of Iowa, Iowa City, IA, USA; b Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; c Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA Plasmacytoid dendritic cells (pDC) are thought to be the main sentinels for viral infections, to which they

We hypothesized that the systemic inflammatory response undergoes two consecutive stages, each characterized by different nonspecific sickness patterns. To test this hypothesis, we studied thermal, nociceptive, and motor responses to lipopolysaccharide (LPS) in 43 unanesthetized, habituated, and lightly restrained male Wistar rats previously implanted with a catheter in the jugular vein. Escherichia coli LPS was injected intravenously in a dose of 0, 0.1, 1, 10, 100, or 1,000 micrograms/kg. Colonic temperature (Tc) was measured with a thermocouple. Changes in nociception were assessed by tail flick latency (TFL) to a noxious heat stimulus. Motor activity was evaluated using an observation-based activity score (AS). The two lowest doses were apyrogenic. The next dose induced a monophasic fever with a maximal Tc rise of 0.9 +/- 0.2 degrees C at 108 +/- 11 min post-LPS. The next two higher doses caused biphasic fevers with the first and second peaks of 0.7 +/- 0.1 and 1.4 +/- 0.1 degrees C (10 micrograms/kg) and 0.7 +/- 0.1 and 1.4 +/- 0.2 degrees C (100 micrograms/kg) occurring at 60 +/- 6 and 165 +/- 17 min and at 45 +/- 3 and 141 +/- 6 min, respectively. The highest dose of LPS resulted in a Tc fall (nadir, -0.6 +/- 0.1 degree C at 83 +/- 6 min). Two different sickness patterns were exhibited. The first (high Tc, low TFL and high AS) occurred during the monophasic fever and the first (early) phase of the biphasic fevers, and it was termed the early phase syndrome. The second pattern (high or low Tc, high TFL, and low AS) developed during the second (late) phase of the biphasic fevers and LPS-hypothermia (endotoxin shock), and it was termed the late phase syndrome. Occurring at different stages of the systemic inflammatory response and developing through different coping patterns [fight/flight (energy expenditure) vs. depression/withdrawal (energy conservation)], the two syndromes represent two different types of adaptation to infection and have different biological significance. Viewing sickness as a dynamic entity is justified clinically. Such a dynamic approach to the problem resolves several contradictions in the current concept of sickness.