Low-energy electron-induced decomposition of 5-trifluoromethanesulfonyl-uracil: A potential radiosensitizer.

5-trifluoromethanesulfonyl-uracil (OTfU), a recently proposed radiosensitizer, is decomposed in the gas-phase by attachment of low-energy electrons. OTfU is a derivative of uracil with a triflate (OTf) group at the C5-position, which substantially increases its ability to undergo effective electron-induced dissociation. We report a rich assortment of fragments formed upon dissociative electron attachment (DEA), mostly by simple bond cleavages (e.g., dehydrogenation or formation of OTf-). The most favorable DEA channel corresponds to the formation of the triflate anion alongside with the reactive uracil-5-yl radical through the cleavage of the O-C5 bond, particularly at about 0 eV. Unlike for halouracils, the parent anion was not detected in our experiments. The experimental findings are accounted by a comprehensive theoretical study carried out at the M06-2X/aug-cc-pVTZ level. The latter comprises the thermodynamic thresholds for the formation of the observed anions calculated under the experimental conditions (383.15 K and 3 × 10-11 atm). The energy-resolved ion yield of the dehydrogenated parent anion, (OTfU-H)-, is discussed in terms of vibrational Feshbach resonances arising from the coupling between the dipole bound state and vibrational levels of the transient negative ion. We also report the mass spectrum of the cations obtained through ionization of OTfU by electrons with a kinetic energy of 70 eV. The current study endorses OTfU as a potential radiosensitizer agent with possible applications in radio-chemotherapy.

Axonal regeneration inhibitors: emerging therapeutic options.

For the most part, the central nervous system is unable to regenerate. The majority of injuries of vascular, inflammatory, degenerative and traumatic aetiology lead to an irreversible loss of central nervous system function. The paper presents the role of Nogo-A, MAG and OMgp proteins in the inhibition of central nervous system regeneration, and their potential clinical significance.

Thermal preferences of wintering snails Planorbarius corneus (L.) exposed to lipopolysaccharide and zymosan.

Fever is regarded as a physiological response to infection both in endothermic and ectothermic animals. In ectotherms, fevers are achieved only behaviorally, and has been described in many vertebrates' and few invertebrates' groups. In snails only symptoms of reverse fever as a response to trematode invasion were found. Present work reports on the effects of two different pyrogens - lipopolysaccharide extracted from Escherichia coli (LPS), and zymosan - from Saccharomyces cerevisiae on the thermal behavior of wintering (studied during a winter season) specimens of the Planorbarius corneus (L.). Using the thermal gradient protocol we demonstrate that the individuals of this snail species responded with behavioral fevers to dosages of pyrogens. LPS injection to the surface of the snail's foot at a dose of 10 µg/g resulted in a significant increase in preferred temperature at 5h after injection. Similarly zymosan at a dose of 0.5 and 1.0 µg/g - caused fever at 8h and 9h respectively. Average temperature chosen by feverish animals after latency period reached 28.7±0.41 °C (LPS), 28.1±0.43 °C (zymosan 1.0 µg/g) or 25.5±0.33 °C (zymosan 0.5 µg/g). We conclude, therefore, that snails are capable of reacting with fever to selected pathogen associated factors, and P. corneus can be used as a model to study a behavioral fever phenomenon in invertebrate animals.

Hypoxia-induced sickness behaviour.

Sickness behaviour (SB) consists of the set of adaptive responses of the host to severe infections and inflammation. It includes, among others, the thermoregulatory responses such as regulated increase (fever) and/or decrease (anapyrexia) of body temperature (T(b)), decrease of motor activity (lethargy), and loss of appetite (hypophagia) resulting in a transient loss of body weight. It is thought that SB is partially induced by the immune-derived mediators such as cytokines and prostaglandins acting on the central nervous system. It has repeatedly been shown, on the other hand, that severe infections (pneumonia, tissue septicemia) can impair processes of the gases exchange both in the lungs and in distal tissues including brain, which may lead to hypoxia of the affected organs. Therefore, we have tested the hypothesis that hypoxia may also provoke SB. The study was conducted on freely moving biotelemetered mice kept at 28 degrees C ambient and 12/12 h light/dark cycle. We demonstrate that mice exposed for 7 days to hypoxia (11%O(2)) displayed all symptoms of SB. Interleukin-6 deficient mice (IL-6 KO) revealed reduced SB symptoms under hypoxic conditions. Recovery of the hypoxia-exposed mice to a normal rhythm in T(b), motor activity and feeding was unaffected by mepacrine, a phospholipase A(2) blocker. The recovery, however, was significantly impaired by indomethacin, a cyclooxygenase inhibitor. Exposure to hypoxemia resulted in significant elevation of plasma IL-6 in both untreated and treated with lipopolysaccharide (LPS) mice. It inhibited, however, a generation of blood prostaglandins (PGE(2)) in mice. Based on these data we conclude that IL-6 and accumulation of free arachidonic acid in biomembranes contribute to hypoxemia- induced SB.

Role of prostaglandins in heme-induced fever.

Brain stroke is often accompanied by a high fever, which is insensitive to a blockade with classic antipyretic drugs known to inhibit the synthesis of prostaglandin E(2) (PGE(2)), a proximal mediator of fever associated with infection. The molecular mechanism of fever associated with stroke is mostly unknown, and has not been thoroughly investigated. One characteristics of the stroke is an extravasation of the erythrocytes into the brain tissue followed by a release of hemoglobin and free heme. In the present study we have tested the hypothesis that free heme itself can induce fever after releasing into the brain. The study was conducted on Sprague Dawley rats instrumented with biotelemetry devices to monitor deep body temperature, and implanted with brain cannulae projected to the lateral ventricle. We demonstrate that heme-L-lysinate microinfused intraventricularly (icv) induces a dose-dependent fever lasting ca. 8 hours. Injection of heme-L-lysinate provoked a significant elevation of PGE(2) in the rat cerebro-spinal fluid collected 3 hours post-injection. The fever induced by heme-L-lysinate was blocked by an icv injection of anti- PGE(2) antibody. It was not affected, however, by intraperitoneal administration of indomethacin, a cyclooxygenase inhibitor. We conclude that heme-induced fever may underlie the stroke fever.

[Effect of lanreotide on prolactin level in patients with pituitary mixed tumors]. / Influence du lanréotide sur la concentration sérique de prolactine chez les patients atteints de tumeurs somato-lactotropes.

Acromegaly is a disease caused by a pituitary tumor (somatotropinoma) or by ectopic secretion of GH or IGF-1. About 15% of tumors secrete not only GH but PRL as well. Last time a lanreotide and an octreotide (the somatostatine analogues) are useful in the therapy of acromegaly. We observed the influence of the lanreotide on GH and prolactin. We noticed that the lanreotide caused not only serum level reduction of a growth hormone but also prolactine in patients with mixed pituitary tumors.

Clinical and cellular effects of cytochrome P-450 modulators.

Stress stimulates the hypothalamic-pituitary-adrenal axis and leads to elevated glucocorticoid hormones (GCs). GCs reduce inflammation and suppress responses mediated by cytokines, including fever and pulmonary inflammation. Besides cyclooxygenases and lipoxygenases, cytochrome P-450 enzymes (CYP), referred to as epoxygenases, are also involved in the metabolism of arachidonic acid, implicating epoxygenases in regulating inflammation and the generation of fever. Intraperitoneal injection of lipopolysaccharide (LPS) triggers fever in rats and mice, and administration of compounds known to induce CYP reduces LPS-induced fever, while inhibitors of CYP suppress fever. Consistent with these findings, inhibitors of CYP augment the elevation of LPS-induced prostaglandin E2 levels, an endogenous pyrogen, and administration of epoxygenase metabolites results in antipyresis. CYP inducers also reduce lung inflammation, the resulting mucous cell metaplasia, and the percentage of Bcl-2-positive mucous cells in rat airways after intratracheal instillation of LPS. Together, these observations indicate that CYP modulators may have therapeutic anti-inflammatory effects, and this pathway may be involved in stress-induced reduction of inflammation.

Role of capsaicin-sensitive afferents in fever and cytokine responses during systemic and local inflammation in rats.

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.

Radiotherapy of testicular intraepithelial neoplasia (TIN): a novel treatment regimen for a rare disease.

PURPOSE: Testicular intraepithelial neoplasia (TIN) is a consistent precursor of most invasive germ cell tumors, currently treated by radiotherapy with 20 Gy, which destroys TIN but preserves Leydig cells. Nevertheless, analysis has shown dose-dependent dysfunction even with low therapeutic doses of 20 Gy in some cases. Therefore, we tested a dose reduction regimen by delivering smaller fractional doses to enhance the tolerance of Leydig cells. METHODS AND MATERIALS: Between 1993 and 1999, 9 patients were treated for TIN in a prospective multicenter trial. A total dose of 13 Gy was administered in 10 fractions of 1.3 Gy. Hormonal levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were assayed serially. RESULTS: During a median follow-up time of 36 months, no patient showed evidence of local disease. A first postradiation biopsy was obtained 3-12 months after radiotherapy; 5 patients underwent a second biopsy 2-3 years after treatment. All biopsies showed a Sertoli cell-only pattern. Follicle-stimulating hormone levels continued to increase 1 year after radiotherapy, signaling eradicated spermiogenesis. Luteinizing hormone and testosterone remained within the normal range 2 years after radiotherapy. CONCLUSIONS: In the treatment of TIN, there seems to be a dose reduction potential to 13 Gy by lowering single fractional doses, which enhances the therapeutic ratio in favor of the Leydig cells.

Effect of heat stress on LPS-induced febrile response in D-galactosamine-sensitized rats.

We have previously reported that heat conditioning augments lipopolysaccharide (LPS)-induced fever in rats, which is accompanied by an accumulation of heat shock protein (HSP) in the liver and the reduction of the plasma level of tumor necrosis factor (TNF-alpha) (Kluger MJ, Rudolph K, Soszynski D, Conn CA, Leon LR, Kozak W, Wallen ES, and Moseley PL. Am J Physiol Regulatory Integrative Comp Physiol 273: R858-R863, 1997). In the present study we have tested whether inhibition of protein synthesis in the liver can reduce the effect of this heat conditioning on the LPS-induced febrile response in the rat. D-galactosamine (D-gal) was used to selectively inhibit liver protein synthesis. D-gal (500 mg/kg) or PBS as control was administered intraperitoneally 1 h before heat stress. LPS (50 microg/kg ip) was injected 24 h post-heat exposure. Treatment with D-gal blunted the febrile response to LPS. Moreover, heat-conditioned rats treated first with D-gal and subsequently with LPS demonstrated a profound fall in core temperature 10--18 h post-LPS. A significant increase of serum TNF-alpha accompanied this effect of D-gal on fever. Heat-conditioned animals receiving D-gal showed an inhibition in inducible HSP-70 in the liver. These data support the role of hepatic function in modulating the febrile response to LPS.

Twelve-year experience with two courses of adjuvant single-agent carboplatin therapy for clinical stage I seminoma.

PURPOSE: During the past 30 years, radiation therapy with 28 to 30 Gy for para-aortic and ipsilateral iliac node areas was the standard adjuvant treatment for clinical stage I seminoma after orchiectomy. However, late effects of radiotherapy prompted a search for alternative adjuvant treatment approaches, including surveillance and application of carboplatin. In this retrospective analysis, we evaluated the efficacy and toxicity of two adjuvant single-agent carboplatin courses in 107 patients who were diagnosed with clinical stage I seminoma at our study centers between 1988 and 1999. PATIENTS AND METHODS: All 107 patients (median age, 39 years; range, 24 to 63 years) received two postoperative adjuvant cycles of carboplatin (400 mg/m(2)). The pathologic tumor stage was pT1 in 84 patients, pT2 in 18 patients, and pT3 in five patients. Whole blood count and serum chemistry were evaluated weekly during treatment to assess hematologic and nonhematologic toxicity. RESULTS: Six patients died from tumor-unrelated causes. The remaining 101 patients are currently alive and free of disease after a median follow-up of 74 months (range, 5 to 145 months). A detailed analysis of hematologic toxicity showed only World Health Organization (WHO) grade 1 leukocytopenia in 10.7% of all cycles and WHO grade 2 leukocytopenia in 2.1% of all cycles. CONCLUSION: Regarding the absence of tumor recurrences in our retrospective analysis and the favorable toxicity profile with no episodes of long-term toxicity, we suggest that two adjuvant courses of single-agent carboplatin for clinical stage I seminoma patients might be equivalent to radiotherapy.

Response of F344 rats to inhalation of subclinical levels of sarin: exploring potential causes of Gulf War illness.

Subclinical, repeated exposures of F344 rats to sarin resulted in brain alterations in densities of chlonergic receptor subtypes that may be associated with memory loss and cognitive dysfunction. The exposures also depressed the immune system. The rat appears to be a good model for studying the effects of subclinical exposure to a nerve gas.

[Value of estradiol, progesterone and cortisol binding globulin (CGB) in patients with laryngeal cancer]. / Poziomy estradiolu, progesteronu i globuliny wiazacej kortyzol (CBG) u chorych na raka krtani.

The unique feature of larynx cancer epidemiology is great discrepance between men and women morbidity. This difference may be explained not only by exposition to environmental factors but also to endogenous one, i.e. sex hormone levels. In 67 patients operated for larynx cancer there were simultaneously estimated the value of estradiol (E2), progesterone (Pg) and cortisol binding globulin (CBG) in blood serum. The radioimmunological assay (RIA) with specific antibodies and antigens signed by J125 was used. Value of hormones and binding globulin were examined by Spectria sets by Orion Diagnostica. The high value of estradiol and CBG in blood serum was observed. In meaningful number of patients we noted normal value of progesterone.

Role of cytochrome P-450 in endogenous antipyresis.

In previous reports, we (15, 18) and others (29) demonstrated data showing that various inhibitors of cytochrome P-450/epoxygenase augment fever in rats and mice, indicating that the enzyme may be involved in endogenous antipyresis. The aim of this study was to further test the hypothesis that the P-450-dependent epoxygenase pathway of arachidonic acid is part of the homeostatic system to control the height of fever. Sprague-Dawley rats were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide (LPS; 80 microg/kg). We demonstrate that intraperitoneal administration of P-450 inducers (bezafibrate and dehydroepiandrosterone, 10 and 100 mg/kg) before LPS reduced fever in rats in a dose-dependent manner. In complementary experiments, rats were implanted with brain cannulas in addition to the biotelemeters. Various isomers of epoxyeicosanoids were administered into the lateral ventricle at doses of 0.01 to 10 microg/rat to test their influence on LPS-induced fever in rats. Four of five isomers were antipyretic in a dose-dependent manner. The most potent antipyretic isomers were 11, 12-epoxyeicosatrienoic acid (EET) followed by 14,15-EET, 8,9-EET, and 12(R) hydroxyeicosatetraenoic acid. These data support the hypothesis that the cytochrome P-450/epoxygenase pathway of arachidonate metabolism is part of the endogenous antipyretic system.

Accumulation of unsaturated lipids in monocytes during early phase pyrogen tolerance.

This paper presents data that inspired a new explanation for the mechanism of early phase endotoxin tolerance. Rabbits injected intravenously with LPS from Salmonella abortus developed a two-phase fever (6 h) and monophasic hyperlipidemia of very low density lipoproteins (two consecutive days). If during these days rabbits were injected with the same dose of LPS at 24-h intervals, the second phase of fever disappeared, i.e. early phase pyrogenic tolerance was obtained. This was correlated with a decrease of lipoprotein hyperlipidemia (measured 1.5 h after LPS injection) and an accumulation of lipids rich in double bonds in monocytes (measured 3.5 h after LPS injection). Results showed that the degree of unsaturation of acyl chains (AC) in monocytes (AC/DB, DB=double bonds) is negatively correlated (r=-0.72) with fever response (fever index). The authors maintain that a gradual increase in monocyte membrane fluidity is an adaptation to repeated exposure of monocytes to lipid A and is responsible for the progressive desensitization of monocytes to endotoxin. It is suggested that disorders of this mechanism lead to an accumulation of abnormal quantities of saturated lipids and cholesterol within macrophages, which, as foam cells, are the starting point for atherosclerosis pathology.

Molecular mechanisms of fever and endogenous antipyresis.

This review summarizes recent studies on endogenous antipyretic mechanisms. Fever is the result of a balance between pyrogenic and cryogenic cytokines and hormones. Although there is considerable evidence that fever evolved as a host defense response, it is important that the rise in body temperature not be too high. Many endogenous cryogens or antipyretics that limit the rise in body temperature have been identified during the last 25 years. These include alpha-MSH, arginine vasopressin, glucocorticoids, TNF (under certain circumstances), and IL-10. Most recently, evidence has accumulated that cytochrome P-450 (P-450), part of the alternative pathway for arachidonic acid metabolism, plays an important role in reduction of fever and inflammation. Supporting a role for P-450 in endogenous antipyresis and antiinflammation includes evidence that (1) inducers of P-450 reduce fever, (2) inhibitors of P-450 cause a larger fever, (3) and P-450 arachidonic acid metabolites reduce fever.

Beta-adrenergic receptor subtype effects on stress fever and thermoregulation.

Exposure to psychological stress increases body temperature (Tb). This stress fever may be immunologically beneficial in some patient populations but detrimental in others (e.g., HIV-infected individuals). For this reason, it is desirable to determine pharmacological methods of preventing stress fever. In rats, stress fever is modeled by exposure to a novel environment or 'open field.' The beta-adrenergic antagonists, nadolol and propranolol, block this stress fever. Neither of these beta-antagonists discriminates between subtypes of beta-receptors. The purpose of this study was to determine the relative contribution of the different beta-receptor types to stress fever using beta1-, beta2-, and beta3-receptor subtype selective antagonists (atenolol [beta1], ICI-118551 [beta2], and SR 59230A [beta3]) and agonists (dobutamine [beta1], salbutamol [beta2], and BRL 37344 [beta3]) on the Tb of rats. Tb was measured with a biotelemetry system. Our data suggest that central nervous system beta-receptor blockade with subtype-selective antagonists prevents the stress-induced rise in Tb; however, the beta3-antagonist was effective only at doses that produced hypothermia in a non-stressed control group. The stress-induced fever was mimicked by central nervous system administration of the selective beta2-agonist, salbutamol, and the beta3-agonist, BRL 37344. We hypothesize that the blockade of stress-induced fever by beta-blockers may be due to the sedative actions of these drugs.

An antipyretic role for interleukin-10 in LPS fever in mice.

Interleukin (IL)-10 inhibits the synthesis of proinflammatory cytokines implicated in fever, including IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. We hypothesized that IL-10 functions as an antipyretic in the regulation of fevers to lipopolysaccharide (LPS) and turpentine. Body temperature was measured by biotelemetry. Swiss Webster (SW) mice treated with recombinant murine IL-10 were resistant to fever induced by a low dose of LPS (100 microgram/kg ip) and to the hypothermic and febrile effects of a high (septiclike) dose of LPS (2.5 mg/kg ip). IL-10 knockout mice developed an exacerbated and prolonged fever in response to a low dose of LPS (50 microgram/kg ip) compared with their wild-type counterparts. At 4 h after injection of the low dose of LPS, plasma levels of IL-6, but not TNF-alpha, were significantly elevated in the IL-10 knockout mice compared with their wild-type controls (ANOVA, P < 0.05). After injection of the same high dose of LPS injected into SW mice, wild-type mice developed a fever at 24 h whereas IL-10 knockout mice immediately developed a profound hypothermia that lasted through 41 h (ANOVA, P < 0.05). Body weight and food intake were more significantly depressed in response to the high dose of LPS in the knockout mice compared with their wild-type controls. Only 30% of the IL-10 knockout mice survived compared with 100% of the wild-type mice (Fisher's exact test, P < 0.05). Fever in response to the injection of turpentine (100 microliter/mouse sc) did not differ between wild-type and IL-10 knockout mice. These data support the hypotheses that 1) IL-10 functions as an endogenous antipyretic following exposure to LPS, 2) a putative mechanism of the early antipyretic action of IL-10 is through the inhibition of plasma levels of IL-6, 3) IL-10 has a protective role in the lethal effects of exposure to high levels of LPS, and 4) endogenous IL-10 does not have a role in fever induced by turpentine.

Inhibitors of alternative pathways of arachidonate metabolism differentially affect fever in mice.

Inhibitors of cyclooxygenases prevent fever. The purpose of this study was to test the hypothesis that selective and dual inhibitors of the other enzyme systems of arachidonic acid oxygenation (i.e., lipoxygenase and epoxygenase) affect the time course or magnitude of fever in mice. Swiss Webster mice kept at 30 degreesC ambient temperature were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide at doses from 10 micrograms/kg to 2.5 mg/kg. Phenidone (20-30 mg/kg ip), a dual lipoxygenase and cyclooxygenase inhibitor, prevented fever in these mice, but esculetin (1-10 mg/kg ip), a selective inhibitor of lipoxygenases, did not affect fever. Intramuscular injection of nordihydroguaiaretic acid (10-20 mg/kg), a dual lipoxygenase and epoxygenase inhibitor, as well as SKF-525A (5 mg/kg ip) and clotrimazole (20 mg/kg im), inhibitors of the cytochrome P-450/epoxygenase pathway, augmented fever in mice. Indomethacin (5 mg/kg ip), an inhibitor of cyclooxygenase, suppressed the exacerbation of fever due to clotrimazole, suggesting that the epoxygenase inhibitor-induced potentiation of fever in mice is a prostaglandin-mediated effect. From this study, we hypothesize that the cytochrome P-450/epoxygenase branch of the arachidonate cascade is involved in antipyresis and in controlling the upper limit of fever.

[Sex-dependence of larynx susceptibility to tobacco smoke carcinogens. The role of androgen hormones]. / Plec a podatnosc krtani na dzialanie czynników kancerogennych obecnych w dymie tytoniowym. Rola hormonów androgennych.

According to epidemiological data concerning laryngeal cancer there is almost ninefold higher morbidity in male population than in females. The aim of this study was to analyse on molecular level the genotoxic effects arising under the same exposure to tobacco smoke in males and females. In biopsies received from laryngectomy material we determined levels of aromatic and alkylated DNA adducts in tumours and in adjacent non-tumour tissue. It was established that levels of DNA adducts found in male DNA samples exceeded those in female DNA samples 1.5-3.8 times, which was recognised as a molecular evidence for epidemiological differences. Next, testosterone and sex hormones binding globulin (SHBG) were determined in male subjects blood serum. The levels of testosterone and SHBG very weakly correlated with DNA adduct levels even when subjects were separated into age groups. It is concluded that levels of testosterone and SHBG are not the proper markers of individual susceptibility to genotoxicity of tobacco smoke carcinogens.