Institute of Physiology National Academy of Sciences of Belarus

A sedentary lifestyle has adverse effects on the cardiovascular system, including impaired endothelial functions. Subjecting healthy men to 7 days of dry immersion (DI) presented a unique opportunity to analyze the specific effects of enhanced inactivity on the endothelium. We investigated endothelial properties before, during, and after 7 days of DI involving eight subjects. Microcirculatory functions were assessed with laser Doppler in the skin of the calf. We studied basal blood flow and endothelium-dependent and -independent vasodilation. We also measured plasma levels of microparticles, a sign of cellular dysfunction, and soluble endothelial factors, reflecting the endothelial state. Basal flow and endothelium-dependent vasodilation were reduced by DI (22 + or - 4 vs. 15 + or - 2 arbitrary units and 29 + or - 6% vs. 12 + or - 6%, respectively, P < 0.05), and this was accompanied by an increase in circulating endothelial microparticles (EMPs), which was significant on day 3 (42 + or - 8 vs. 65 + or - 10 EMPs/microl, P < 0.05), whereas microparticles from other cell origins remained unchanged. Plasma soluble VEGF decreased significantly during DI, whereas VEGF receptor 1 and soluble CD62E were unchanged, indicating that the increase in EMPs was associated with a change in antiapoptotic tone rather than endothelial activation. Our study showed that extreme physical inactivity in humans induced by 7 days of DI causes microvascular impairment with a disturbance of endothelial functions, associated with a selective increase in EMPs. Microcirculatory endothelial dysfunction might contribute to cardiovascular deconditioning as well as to hypodynamia-associated pathologies. In conclusion, the endothelium should be the focus of special care in situations of acute limitation of physical activity.

Receptors for extracellular ATP (both ionotropic and metabotropic) are widely expressed in the CNS both in neurones and glia. ATP can modulate neuronal activity in many parts of the brain and contributes to the central nervous control of several physiological functions. Here we show that during the systemic inflammatory response the extracellular concentrations of ATP increase in the anterior hypothalamus and this has a profound effect on the development of the thermoregulatory febrile response. In conscious rabbits we measured ATP release in real time with novel amperometric biosensors and monitored a marked increase in the concentration of ATP (4.0 +/- 0.7 microm) in the anterior hypothalamus in response to intravenous injection of bacterial endotoxin - lipopolysaccharide (LPS). No ATP release was observed in the posterior hypothalamus. The release of ATP coincided with the development of the initial phase of the febrile response, starting 18 +/- 2 min and reaching its peak 45 +/- 2 min after LPS injection. Application of the ATP receptor antagonists pyridoxal-5'-phosphate-6-azophenyl-2',4'-disulphonic acid, Brilliant Blue G or periodate oxidized ATP dialdehyde to the site of ATP release in the anterior hypothalamus markedly augmented and prolonged the febrile response. These data indicate that during the development of the systemic inflammation, ATP is released in the anterior hypothalamus to limit the magnitude and duration of fever. This release may also have a profound effect on the hypothalamic control of other physiological functions in which ATP and related purines have been implicated to play modulatory roles, such as food intake, hormone secretion, cardiovascular activity and sleep.

As pretreatment with intraperitoneal capsaicin (8-methyl-N-vanillyl-6-nonenamide, CAP), an agonist of the vanilloid receptor known as VR1 or transient receptor potential channel-vanilloid receptor subtype 1 (TRPV-1), has been shown to block the first phase of lipopolysaccharide (LPS) fever in rats, this phase is thought to depend on the TRPV-1-bearing sensory nerve fibers originating in the abdominal cavity. However, our recent studies suggest that CAP blocks the first phase via a non-neural mechanism. In the present work, we studied whether this mechanism involves the TRPV-1. Adult Long-Evans rats implanted with chronic jugular catheters were used. Pretreatment with CAP (5 mg kg(-1), i.p.) 10 days before administration of LPS (10 microg kg(-1), i.v.) resulted in the loss of the entire first phase and a part of the second phase of LPS fever. Pretreatment with the ultrapotent TRPV-1 agonist resiniferatoxin (RTX; 2, 20, or 200 microg kg(-1), i.p.) 10 days before administration of LPS had no effect on the first and second phases of LPS fever, but it exaggerated the third phase at the highest dose. The latter effect was presumably due to the known ability of high doses of TRPV-1 agonists to cause a loss of warm sensitivity, thus leading to uncontrolled, hyperpyretic responses. Pretreatment with the selective competitive TRPV-1 antagonist capsazepine (N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamidem, CPZ; 40 mg kg(-1), i.p.) 90 min before administration of LPS (10 microg kg(-1), i.v.) or CAP (1 mg kg(-1), i.p.) did not affect LPS fever, but blocked the immediate hypothermic response to acute administration of CAP. It is concluded that LPS fever is initiated via a non-neural mechanism, which is CAP-sensitive but RTX- and CPZ-insensitive. The action of CAP on this mechanism is likely TRPV-1-independent. It is speculated that this mechanism may be the production of prostaglandin E(2) by macrophages in LPS-processing organs.

Hypothermia occurs in the most severe cases of systemic inflammation, but the mechanisms involved are poorly understood. This study evaluated whether the hypothermic response to bacterial lipopolysaccharide (LPS) is modulated by the endocannabinoid anandamide(AEA) and its receptors: cannabinoid-1 (CB1), cannabinoid-2 (CB2) and transient receptor potential vanilloid-1 (TRPV1). In rats exposed to an ambient temperature of 22◦C, a moderate dose of LPS (25 - 100 μg kg−1 I.V.) induced a fall in body temperature with a nadir at ∼100 minpostinjection. This response was not affected by desensitization of intra-abdominal TRPV1 receptors with resiniferatoxin (20 μg kg - 1 I.P.), by systemic TRPV1 antagonism with capsazepine(40mg kg−1 I.P.), or by systemic CB2 receptor antagonism with SR144528 (1.4 mg kg−1 I.P.).However, CB1 receptor antagonism by rimonabant (4.6mg kg−1 I.P.) or SLV319 (15mg kg−1 I.P.)blocked LPS hypothermia. The effect of rimonabant was further studied. Rimonabant blocked LPS hypothermia when administered I.C.V. at a dose (4.6 μg) that was too low to produce systemic effects. The blockade of LPS hypothermia by I.C.V. rimonabant was associated with suppression of the circulating level of tumour necrosis factor-α. In contrast to rimonabant,the I.C.V. administration of AEA (50 μg) enhanced LPS hypothermia. Importantly, I.C.V. AEAdid not evoke hypothermia in rats not treated with LPS, thus indicating that AEA modulates LPS-activated pathways in the brain rather than thermo effector pathways. In conclusion, the present study reveals a novel, critical role of brain CB1 receptors in LPS hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis.

Research concerning new targeting delivery systems for pharmacologically active molecules and genetic material is of great importance. The aim of the present study was to investigate the potential of fourth generation (P4) cationic phosphorus-containing dendrimers to bind fluorescent probe 8-anilino-1-naphthalenesulfonate (ANS), anti-neoplastic drug cisplatin, anti-HIV siRNA siP24 and its capability to deliver green fluorescent protein gene (pGFP) into cells. The interaction between P4 and ANS (as the model drug) was investigated. The binding constant and the number of binding centers per one molecule of P4 were determined. In addition, the dendriplex between P4 and anti-HIV siRNA siP24 was characterized using circular dichroism, fluorescence polarization and zeta-potential methods; the average hydrodynamic diameter of the dendriplex was calculated using zeta-size measurements. The efficiency of transfection of pGFP using P4 was determined in HEK293 cells and human mesenchymal stem cells, and the cytotoxicity of the P4-pGFP dendriplex was studied. Furthermore, enhancement of the toxic action of the anti-neoplastic drug cisplatin by P4 dendrimers was estimated. Based on the results, the fourth generation cationic phosphorus-containing dendrimers seem to be a good drug and gene delivery carrier candidate.

Although the involvement of blood-borne PGE2 in fever has been hypothesized by several authors and has substantial experimental support, the current literature often rejects this hypothesis because several attempts to induce fever by a peripheral PGE2 failed. However, it is usually ignored that the amphipathic molecules of PGE2 are readily self-associating and that such an aggregation could have prevented the peripherally administered PGE2 (free form) from expressing its pyrogenic activity, thus leading to false negative results. To ensure disaggregation of PGE2, we prepared its complex within a carrier protein, human serum albumin (HSA). HSA was purified with activated charcoal and polymixin B-polyacrylamide gel and incubated with PGE2 for 1 h at 37 degrees C. Adult Chinchilla rabbits were injected intravenously with PGE2-HSA complex in either the higher (75 micrograms/kg PGE2:30 mg/kg HSA) or the lower (15 micrograms/kg:6 mg/kg) dose, and the rectal temperature (Tr) was measured. In the controls, either the ligand alone or the carrier alone was administered. At the higher dose, neither free PGE2 nor albumin alone was pyrogenic, whereas the PGE2-HSA complex produced a fever characterized by a short latency (<10 min) and a maximal Tr rise of 0.7 +/- 0.2 degrees C. At the lower dose, none of the substances affected the Tr. This study demonstrates a marked pyrogenic activity of the intravenous PGE2-HSA, but not of the free PGE2. Administration of a preformed complex may be more physiologically relevant than administration of the free ligand because of the ligand's disaggregation, protection from enzymatic degradation, and facilitated delivery to targets. Our study supports the hypothesis that peripheral PGE2 is involved in fever genesis.

Adenosine 5′‐triphosphate (ATP) has been shown to induce release of cytokines implicated in fever, including interleukin(IL)‐1 β , IL‐6, and tumour necrosis factor‐ α (TNF‐ α ). The role of ATP‐mediated purinergic signalling in fever and cytokine release during systemic inflammation was investigated by studying the effects of P2 receptor antagonists suramin, pyridoxal‐5′‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS), and Brilliant Blue G (BBG) on changes in body temperature and the increases in plasma levels of IL‐1 β , IL‐6, and TNF α induced by bacterial lipopolysaccharide (LPS) in rats. LPS ( Escherichia coli ; 50 μ g kg −1 )‐induced febrile response was attenuated by suramin (25 mg kg −1 and 100 mg kg −1 ), PPADS (25 mg kg −1 ), and a more selective P2X 7 receptor antagonist BBG (100 mg kg −1 ) injected intraperitoneally before the induction of fever. The increase in plasma concentrations of IL‐1 β and IL‐6, measured 1 h after LPS treatment, was reduced by PPADS (25 mg kg −1 ) and BBG (100 mg kg −1 ). LPS‐induced increase in plasma TNF‐ α concentration was also markedly attenuated by BBG (100 mg kg −1 ), but not by PPADS (25 mg kg −1 ). These data indicate that purinergic signalling plays an important role in the mechanisms responsible for the LPS‐induced febrile response and increases in the levels of circulating cytokines. We suggest that ATP acting via P2X 7 receptors induces release of pyrogenic cytokines to mediate fever during systemic inflammation. British Journal of Pharmacology (2005) 146 , 139–145. doi: 10.1038/sj.bjp.0706287

has been defended for the sake of tradition and gastronomy. Hunters argued that ortolan buntings trapped in southwest France originate from large and stable populations across the whole of Europe. Yet, the European Commission referred France to the Court of Justice of the European Union (EU) in December 2016 for infringements to legislation (IP/16/4213). To better assess the impact of hunting in France, we combined Pan-European data from archival light loggers, stable isotopes, and genetics to determine the migration strategy of the species across continents. Ortolan buntings migrating through France come from northern and western populations, which are small, fragmented and declining. Population viability modeling further revealed that harvesting in southwest France is far from sustainable and increases extinction risk. These results provide the sufficient scientific evidence for justifying the ban on ortolan harvesting in France.

Epilepsy is a challenging brain disorder that is often difficult to treat with conventional therapies. The gut microbiota has been shown to play an important role in the development of neuropsychiatric disorders, including epilepsy. In this study, the effects of Bifidobacterium longum, a probiotic, on inflammation, neuronal degeneration, and behavior are evaluated in a lithium–pilocarpine model of temporal lobe epilepsy (TLE) induced in young adult rats. B. longum was administered orally at a dose of 109 CFU/rat for 30 days after pilocarpine injection. The results show that B. longum treatment has beneficial effects on the TLE-induced changes in anxiety levels, neuronal death in the amygdala, and body weight recovery. In addition, B. longum increased the expression of anti-inflammatory and neuroprotective genes, such as Il1rn and Pparg. However, the probiotic had little effect on TLE-induced astrogliosis and microgliosis and did not reduce neuronal death in the hippocampus and temporal cortex. The study suggests that B. longum may have a beneficial effect on TLE and may provide valuable insights into the role of gut bacteria in epileptogenesis. In addition, the results show that B. longum may be a promising drug for the comprehensive treatment of epilepsy.

1. P2 purinoreceptors are present in hypothalamic and brainstem nuclei that are involved in the regulation of body temperature (T(b)). The role of ATP acting on these P2 receptors in thermoregulation was investigated by studying the effects of the stable ATP analogue alpha,beta-methyleneATP (alpha,beta-meATP) and P2 receptor antagonists suramin and pyridoxal-5'-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on T(b) when injected intracerebroventricularly (i.c.v.) via a pre-implanted cannula in conscious rats at various ambient temperatures and during lipopolysaccharide (LPS)-induced fever. 2. Depending on ambient temperature, alpha,beta-meATP (0.2 micromol, i.c.v.) induced a fall in T(b) (-3.3 degrees C, P<0.05), no changes in T(b) when compared to pre-injection levels, or an increase in T(b) ( approximately 1.0 degrees C, P<0.05) in rats maintained at 10 degrees C, 25 degrees C and 30 degrees C ambient temperature, respectively. 3. Suramin (7 nmol, i.c.v.) induced a lasting (up to 6 h) increase in T(b) (on average 1.2 degrees C, P<0.05) in rats kept at 25 degrees C or 30 degrees C, but failed to induce any rise in T(b) in rats at 10 degrees C ambient temperature. An increase in T(b) was also observed in rats (25 degrees C ambient temperature) treated with PPADS (0.2 micromol, i.c.v.). 4. alpha,beta-meATP (0.2 micromol) injected i.c.v. or directly into the anterior hypothalamus caused a profound fall in T(b) (by 0.9 degrees C and 1.0 degrees C, respectively; P<0.05) during LPS (E.coli; 50 microg kg(-1))-induced fever in rats at 25 degrees C ambient temperature. Fever was initiated more rapidly in rats treated with suramin (7 nmol) or PPADS (70 nmol), however its late phase was unaffected. Suramin (7 nmol) and PPADS (70 nmol) injected at the time when fever was already developed (2.5 h after LPS injections) did not alter febrile T(b). 5. These data indicate that purinergic signalling may play a significant role in central mechanisms of T(b) regulation at various ambient temperatures and during fever.

Alpha(2)-macroglobulin (alpha(2)M) is not only a proteinase inhibitor in mammals, but it is also a specific cytokine carrier that binds pro- and anti-inflammatory cytokines implicated in fever, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). To define the role of alpha(2)M in regulation of febrile and cytokine responses, wild-type mice and mice deficient in alpha(2)M (alpha(2)M -/-) were injected with lipopolysaccharide (LPS). Changes in body temperature as well as plasma levels of IL-1beta, IL-6, and TNF-alpha and hepatic TNF-alpha mRNA level during fever in alpha(2)M -/- mice were compared with those in wild-type control mice. The alpha(2)M -/- mice developed a short-term markedly attenuated (ANOVA, P < 0.05) fever in response to LPS (2.5 mg/kg ip) compared with the wild-type mice. At 1.5 h after injection of LPS, the plasma concentration of TNF-alpha, but not IL-1beta or IL-6, was significantly lower (by 58%) in the alpha(2)M -/- mice compared with their wild-type controls (ANOVA, P < 0.05). There was no difference in hepatic TNF-alpha mRNA levels between alpha(2)M -/- and wild-type mice 1.5 h after injection of LPS. These data support the hypotheses that 1) alpha(2)M is important for the normal development of LPS-induced fever and 2) a putative mechanism of alpha(2)M involvement in fever is through the inhibition of TNF-alpha clearance. These findings indicate a novel physiological role for alpha(2)M.

The limited specificity of nanoparticle (NP) uptake by target cells associated with a disease is one of the principal challenges of nanomedicine. Using the threshold mechanism of plasmonic nanobubble (PNB) generation and enhanced accumulation and clustering of gold nanoparticles in target cells, we increased the specificity of PNB generation and detection in target versus non-target cells by more than one order of magnitude compared to the specificity of NP uptake by the same cells. This improved cellular specificity of PNBs was demonstrated in six different cell models representing diverse molecular targets such as epidermal growth factor receptor, CD3 receptor, prostate specific membrane antigen and mucin molecule MUC1. Thus PNBs may be a universal method and nano-agent that overcome the problem of non-specific uptake of NPs by non-target cells and improve the specificity of NP-based diagnostics, therapeutics and theranostics at the cell level.

Zika virus (ZIKV) spread led to the recent medical health emergency of international concern. Understanding the variations in virus system is of utmost need. Using available complete sequences of ZIKV we estimated directions of mutational pressure along the length of consensus sequences of three lineages of the virus. Results showed that guanine usage is growing in ZIKV RNA plus strand due to adenine to guanine transitions, while adenine usage is growing due to cytosine to adenine transversions. Especially high levels of guanine have been found in two-fold degenerated sites of certain areas of RNA plus strand with high amount of secondary structure. The usage of cytosine in two-fold degenerated sites shows direct dependence on the amount of secondary structure in 52% (consensus sequence of East African ZIKV lineage)-32% (consensus sequence of epidemic strains) of the length of RNA minus strand. These facts are the evidences of ADAR-editing of both strands of ZIKV genome during pauses in replication. RNA plus strand can also be edited by ADAR during pauses in translation caused by the appearance of groups of rare codons. According to our results, RNA minus strand of epidemic ZIKV strain has lower number of points in which polymerase can be stalled (allowing ADAR-editing) compared to other strains. The data on preferable directions of mutational pressure in epidemic ZIKV strain is useful for future vaccine development and understanding the evolution of new strains.

Instead of relying on external anticancer factors for treatment, immunotherapy utilizes the host's own immune system and directs it against given tumour antigens. This study demonstrated that it is possible to overcome the documented immunosuppressive properties of tumour cell lysate by supplementing it with appropriate adjuvant. Lewis lung carcinoma (LLC)‑challenged C57BL/6 mice were treated with LLC cryo‑lysate mixed with either bacterial ghosts (BGs) generated from E. coli Nissle 1917 or B. subtilis 70 kDa protein as adjuvants. Median and overall survival, the size of metastatic foci in lung tissue and levels of circulating CD8a+ T cells were evaluated and compared to the untreated control mice or mice treated with LLC lysate alone. After primary tumour removal, a course of three subcutaneous vaccinations with LLC lysate supplemented with BGs led to a significant increase in overall survival (80% after 84 days of follow‑up vs. 40% in untreated control mice), a significant increase in circulating CD8a+ T cells (16.57 vs. 12.6% in untreated control mice) and a significant decrease in metastasis foci area and incidence. LLC lysate supplemented with B. subtilis protein also improved the inspected parameters in the treated mice, when compared against the untreated control mice, but not to a significant degree. Therefore, whole cell lysate supplemented with BGs emerges as an immunostimulatory construct with potential clinical applications in cancer treatment.

The present article is devoted to problems pertaining to the combined (simultaneous) medical application of the therapeutic physical factors. The classification of the methods used in combined physical therapy is proposed, their advantages over the traditional therapeutic modalities are discussed, the general principles of simultaneous application of the medical physical factors are considered. The possible variants of interaction between such physical factors in the case of their combined application are theoretically determined, the criteria for their quantitative assessment (coefficients of synergism and effectiveness of combination) are offered, examples of their application for the evaluation of the efficiency of the selected combinations are provided.

The very forward region of a detector at a linear e/sup +/e/sup -/ collider is a particularly challenging area for instrumentation. In the TESLA detector, two calorimeters, BeamCal (Beam Calorimeter) and LumiCal (Luminosity Calorimeter) are planned. The BeamCal is positioned just adjacent to the beampipe. It will be hit by beamstrahlung remnants giving a deposition of several tens of TeV per bunch crossing. The distribution of this energy will be measured to assist in tuning the beams. Single high-energy electrons will be identified and measured. High-energy electron identification is particularly important to veto backgrounds to new particle searches. Several technological options for BeamCal are discussed. Monte Carlo simulations are presented for a diamond/tungsten sandwich structure and compared to results obtained for a heavy element crystal calorimeter. First, tests of sensors are described. The LumiCal will measure larger polar angles than the BeamCal. It will provide a high-precision (O(10/sup -4/)) luminosity measurement from Bhabha scattering. Monte Carlo simulations to optimize the shape and the structure of the calorimeter are presented.

BACKGROUND: The aim of this population-based study was to evaluate the clinical and pathological characteristics and outcome of papillary thyroid carcinoma (PTC) that have arisen in the Belarusian childhood population exposed to the radioactive fallout from the Chernobyl accident within a long-term period. PATIENTS AND METHODS: The long-term treatment results were investigated in 1078 children and adolescents (<19 years old) with PTC who were surgically treated during the years 1990 through 2005. RESULTS: Patients had high rates of metastatic PTC at presentation, with 73.8% of cases having lymph node involvement and 11.1% having distant spread. The most influential factor for lymph node metastases at initial treatment was lymphatic vessel invasion (P < .0001) and for distant metastases, lateral lymph node involvement (P < .0001). The overall survival was 96.9% ± 0.9% with a median follow-up of 16.21 years, and 20-year event-free survival and relapse-free survival were 87.8% ± 1.6% and 92.3% ± 0.9%, respectively. Patients had significantly lower probability of both loco-regional (P < .001) and distant relapses (P = .005) after total thyroidectomy (TT) and radioactive iodine therapy (RAI). For loco-regional relapses after TT, only RAI influenced the prognosis significantly (P < .001). For distant relapses after TT, the refusal to treat with RAI (hazard ratio [HR] = 9.26), vascular invasion (HR = 8.68), and age at presentation (HR = 6.13) were significant risk factors. For loco-regional relapses after non-TT, the principal risk factors were age less than 15 years old at presentation (HR = 5.34) and multifocal growth of tumor (HR = 5.19). For distant relapses after non-TT, the lateral neck metastases were the only unfavorable factor (HR = 9.26). CONCLUSION: The outcome of PTC both in children and in adolescents exposed to the post-Chernobyl radioiodine fallout was rather favorable. TT with RAI is recommended for minimizing loco-regional or distant relapses.

We registered surface enhanced Raman scattering (SERS) spectra of the human lactoferrin molecules adsorbed on a silvered porous silicon (por-Si) from 10−6–10−18 M solutions. It was found that the por-Si template causes a negative surface potential of silver particles and their chemical resistivity to oxidation. These properties provided to attract positively charged lactoferrin molecules and prevent their interaction with metallic particles upon 473 nm laser excitation. The SERS spectra of lactoferrin adsorbed from 10−6 M solution were rather weak but a decrease of the concentration to 10−10 M led to an enormous growth of the SERS signal. This effect took place as oligomers of lactoferrin were broken down to monomeric units while its concentration was reduced. Oligomers are too large for a uniform overlap with electromagnetic field from silver particles. They cannot provide an intensive SERS signal from the top part of the molecules in contrast to monomers that can be completely covered by the electromagnetic field. The SERS spectra of lactoferrin at the 10−14 and 10−16 M concentrations were less intensive and started to change due to increasing contribution from the laser burned molecules. To prevent overheating the analyte molecules on the silvered por-Si were protected with graphene, which allowed the detection of lactoferrin adsorbed from the 10−18 M solution.

OBJECTIVE: Peripheral afferents play an important role in fever. In the present study, we investigated the role of capsaicin-sensitive afferents in fever and cytokine responses during systemic (induced by intraperitoneal lipopolysaccharide, LPS) and local (induced by injection of Freund's incomplete adjuvant, FIA, into the paw) inflammation. METHODS: Fevers in rats (8-10 weeks of age) whose capsaicin-sensitive afferents were depleted by neonatal capsaicin (50 mg/kg) treatment were compared to those of rats treated as neonates with vehicle. To investigate a possible involvement of cytokines, plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured during LPS- and FIA-induced fever in rats after capsaicin-induced desensitization. Body temperature was measured by biotelemetry. IL-6 and TNF bioactivities in plasma were determined using bioassays. RESULTS: The initial but not the late phase of LPS (50 microg/kg)-induced fever was markedly higher (approximately 1.0 degree C) in rats whose capsaicin-sensitive neurons were destroyed by neonatal capsaicin treatment. Capsaicin-induced desensitization also resulted in significantly higher plasma levels of IL-6 and TNF 1 but not 4 h after LPS challenge. In contrast, the day after injection with FIA (0.1 ml), rats treated with capsaicin had significantly lower body temperatures compared with vehicle-treated animals. No differences were found in plasma levels of IL-6 and TNF between capsaicin- and vehicle-treated animals in response to FIA. CONCLUSIONS: These data indicate that the role of capsaicin-sensitive afferents in fever depends on the type of inflammatory response. During systemic inflammation, capsaicin-sensitive afferents may be involved in modulating fever by regulating the levels of pyrogenic cytokines. During local inflammation, the late phase of fever is partially mediated via capsaicin-sensitive afferents.

Systemic inflammatory response syndrome is associated with either fever or hypothermia, but the mechanisms responsible for switching from one to the other are unknown. In experimental animals, systemic inflammation is often induced by bacterial lipopolysaccharide (LPS). To identify the diencephalic and brainstem structures involved in the fever-hypothermia switch, we studied the expression of c-Fos protein, a marker of neuronal activation, in rats treated with the same high dose of LPS (0.5 mg/kg, intravenously) either in a thermoneutral (30 °C) or cool (24 °C) environment. At 30 °C, LPS caused fever; at 24 °C, the same dose caused profound hypothermia. Both fever and hypothermia were associated with the induction of c-Fos in many brain areas, including several structures of the anterior preoptic, paraventricular, lateral, and dorsal hypothalamus, the bed nucleus of the stria terminalis, the posterior pretectal nucleus, ventrolateral periaqueductal gray, lateral parabrachial nucleus, area postrema, and nucleus of the solitary tract. Every brain area studied showed a comparable response to LPS at the two different ambient temperatures used, with the exception of two areas: the dorsomedial hypothalamic nucleus (DMH), which we studied together with the adjacent dorsal hypothalamic area (DA), and the paraventricular hypothalamic nucleus (PVH). Both structures had much stronger c-Fos expression during LPS hypothermia than during fever. We propose that PVH and DMH/DA neurons are involved in a circuit, which - depending on the ambient temperature - determines whether the thermoregulatory response to bacterial LPS will be fever or hypothermia.