Insight into the Chemistry of PETN Under Shock Compression Through Ultrafast Broadband Mid-Infrared Absorption Spectroscopy.

Thin films of pentaerythritol tetranitrate (PETN) were shock compressed using the laser driven shock apparatus at Los Alamos National Laboratory (LANL). Two spectroscopic probes were available to this apparatus: visible white light transient absorption spectroscopy (VIS) from 400 to 700 nm and mid-infrared transient absorption spectroscopy (MIR) from 1150 to 3800 cm-1. Important PETN vibrational modes are the symmetric and antisymmetric NO2 stretches at 1280 and 1650 cm-1, respectively, as well as CH stretches at ∼2900 cm-1. Shock strength was varied from approximately 3 to 55 GPa to span from the chemically unreactive regime to the regime in which fast chemical reaction took place on the 250 ps time scale of the measurements. VIS and MIR results suggest irreversible chemistry was induced in PETN at pressures above 30 GPa. At lower shock pressures, the spectroscopy showed minimal changes attributable to pressure induced effects. Under the higher-pressure reactive conditions, the frequency region at the antisymmetric NO2 stretch mode had a significantly increased absorption while the region around the symmetric NO2 stretch did not. No observable increased absorption occurred in the higher frequency regions where CH-, NH-, and OH- bond absorptions would be observed. A broad absorption appeared on the shoulder at the red-edge of the CO2 vibrational band around 2200 cm-1. In addition to the experiments, reactive molecular dynamics were carried out under equivalent shock conditions to correlate the evolution of the infrared spectrum to molecular processes. The simulations show results consistent to experiments up to 30 GPa but suggest that NO and NO2 related features provided the strongest contributions to the shocked infrared changes. Proposed mechanisms for shocked PETN chemistry are analyzed as consistent or inconsistent with the data presented here. Our experimental data suggests C≡O or N2O bond formation, nitrite formation, and absence of significant hydroxyl or amine concentrations in the initial chemistry steps in PETN shocked above 30 GPa.

Validation of a short questionnaire for estimating dietary calcium intakes.

UNLABELLED: Concern about calcium supplements, and mainly minor side effects (e.g. constipation) impacting on compliance, means that assessing dietary calcium intake is important. There is no suitable biomarker. Compared to food diaries, a short questionnaire was an efficient way of confirming that patients had adequate calcium intakes (>700 or >1,000 mg) INTRODUCTION: Calcium is usually given alongside treatments for osteoporosis, but recent concerns about potential side effects have led to questioning whether supplements are always necessary. It is difficult to assess calcium intake in a clinical setting and be certain that the patient is getting enough calcium. The aim of this study was to determine whether a short questionnaire for estimating dietary calcium intakes in a clinical setting was fit for purpose. METHODS: We assessed dietary calcium intakes using a short questionnaire (CaQ) in patients attending an osteoporosis clinic (n = 117) and compared them with calcium intakes obtained from a 7-day food diary (n = 72) and a food frequency questionnaire (FFQ) (n = 33). RESULTS: Mean (SD) daily calcium intakes from the CaQ were 836 (348) mg; from the diaries, 949 (384) mg; and from the FFQ, 1,141 (387) mg. The positive predictive value (PPV) was >80% for calcium cut-offs > 700 mg and 70% for cut-offs > 1,000 mg. The calcium intakes for the false positives results were not far below the cut-off. For 1,200 mg, the PPV was 67% or less. CONCLUSION: The CaQ is an adequate tool for assessing whether a patient has daily calcium intakes above 700 or 1,000 mg; if below these cut-offs, it is possible that the patient still has enough calcium in the diet, which could be clarified by questioning the patient further. As there were few patients with calcium intakes above 1,200 mg a day, the CaQ cannot be recommended as a tool for confirming higher dietary calcium intakes.

Paroxetine administration failed [corrected] to influence human exercise capacity, perceived effort or hormone responses during prolonged exercise in a warm environment.

The purpose of the experiment was to examine whether selective serotonin (5-HT) re-uptake transporter blockade by paroxetine has any effect on perceived effort (RPE) during exercise or the time to reach volitional fatigue and on the prolactin and cortisol responses during prolonged exercise performed in a warm environment. Eight healthy males performed two cycle rides to exhaustion in a warm (32 degrees C) environment at 60% of maximum oxygen uptake. Paroxetine (20 mg) or placebo was administered 5 h before exercise trials in a randomised double blind fashion. Time to exhaustion was not significantly influenced by administration of paroxetine: median (range) time to exhaustion was 93.3 (76.2-175.0) min on the placebo trial and 92.5 (66.0-151.0) min on the paroxetine trial. Rectal temperature was higher at rest and throughout exercise on the paroxetine trial. The serum concentrations of prolactin and cortisol were determined throughout exercise as peripheral markers of central 5-HT activity. RPE increased over time but was not influenced by paroxetine administration. Prolactin and cortisol levels increased over time but paroxetine administration did not influence the hormone responses during exercise. In conclusion, acute administration of paroxetine failed to alter RPE, exercise capacity or the response of the determined peripheral hormone markers of central 5-HT activity during prolonged exercise in a warm environment.

Hyperprolactinaemia during prolonged exercise in the heat: evidence for a centrally mediated component of fatigue in trained cyclists.

Several lines of evidence suggest that central serotoninergic neurons may mediate fatigue signals during prolonged exercise. In this study we examined the effects of diet and ambient temperature on peripheral modulators and indices of serotoninergic function and their relationship to exercise performance. Six well-trained cyclists participated, in randomised order, in two diet and exercise regimens each lasting 8 days and comprising four cycle tests to exhaustion at 70 % of maximum oxygen uptake. On days 1 and 5, subjects exercised to exhaustion to deplete muscle glycogen. For 3 days after the first depletion trial a diet providing 10 % of energy in the form of carbohydrate (CHO) was consumed (low CHO), and for 3 days after the second depletion trial a diet providing 80 % (high CHO) of energy as CHO was consumed, and each diet was followed by a performance trial at the same ambient temperature, either 10 degrees C or 30 degrees C (days 4 and 8). This schedule was repeated after 1 week, but performance trials were carried out at the other ambient temperature. In the cold, cycling time increased (P < 0.01) from 89.2 (78.0-129.5) min (median (range)) in the low CHO trial to 158.2 (116.9-165.6) min in the high CHO trial. In the heat, cycling time increased from 44.0 (31.8-51.4) min in the low CHO trial to 53.2 (50.2-82.2) min on the high CHO trial (P = 0.02). The serum prolactin (Prl) concentration was higher at exhaustion during the two trials in the heat than in the two trials in the cold. Serum Prl levels were unrelated to the purported peripheral modulators of serotoninergic function (plasma concentrations of total tryptophan (Trp), free Trp, branched-chain amino acids (BCAAs), free Trp/BCAA ratio and total Trp/BCAA ratio) but were significantly related to the rectal temperatures measured during the two trials in the heat. This finding provides indirect evidence that the serotoninergic system may be involved in fatigue during exercise under conditions of heat stress.

Inhibition of immune-complex mediated dermal inflammation in rats following either oral or topical administration of a small molecule C5a receptor antagonist.

1. Initiation of a peritoneal Arthus reaction by deposition of immune-complexes results in vascular leakage, polymorphonuclear leukocyte (PMN) infiltration, and tumour necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production. We now demonstrate in rats that oral administration of the C5a receptor antagonist AcPhe[Orn-Pro-D-Cyclohexylalanine-Trp-Arg] (AcF-[OPdChaWR]; 1 - 10 mg kg(-1) 30 min prior to immune-complex deposition) inhibits these inflammatory markers in the peritoneal Arthus reaction. 2. Initiation of a dermal Arthus reaction resulted in a significant increase in vascular leakage, PMN infiltration, systemic production of TNFalpha and pathological changes in the dermis. 3. Pretreatment of rats with AcF-[OPdChaWR] either intravenously (1 mg kg(-1) 10 min prior to immune-complex deposition) or orally (1 - 10 mg kg(-1) 30 min prior to immune-complex deposition) significantly inhibited immune-complex mediated dermal vascular leakage and systemic cytokine production. Topical pretreatment with AcF-[OPdChaWR] (400 microg site(-1) in 10% dimethyl sulphoxide 10 min prior to immune-complex deposition) also inhibited vascular leakage, as well as histopathological changes associated with a dermal Arthus reaction. 4. Oral administration of 3 mg kg(-1) AcF-[OPdChaWR] resulted in the appearance of the drug in plasma within 5 min, with peak blood levels approximately 0.3 microM reached within 20 min. The plasma elimination half-life was approximately 70 min. The oral activity and bioavailability of AcF-[OPdChaWR], its activity when applied topically to the skin, suggest that small molecule C5a receptor antagonists may have therapeutic utility in dermal inflammatory disorders involving complement activation. 5. This is the first demonstration for either an orally or topically active C5a receptor antagonist, and suggests that small molecule C5a antagonists may have therapeutic utility when given by multiple routes of application.

Anaesthesia for stent graft repair of thoracic aneurysm and coarctation of the aorta.

We present the anaesthetic management of a patient for stenting of a thoracic aortic aneurysm at the site of an aortic coarctation. The specific challenges to the anaesthetist for this case are outlined. These include the specific problems of placing the graft, the obvious risk of aortic rupture and the unfamiliar environment of the separate radiological theatre. The advantages and disadvantages to the anaesthetist of the treatment of thoracic aortic aneurysms with stents are briefly discussed.

Species dependence for binding of small molecule agonist and antagonists to the C5a receptor on polymorphonuclear leukocytes.

This study investigated the receptor binding affinities of a C5a agonist and cyclic antagonists for polymorphonuclear leukocytes (PMNs) isolated from human, sheep, pig, dog, rabbit, guinea pig, rat and mouse. The affinities of the two small molecule antagonists, F-[OPdChaWR] and AcF-[OPdChaWR], and the agonist, YSFKPMPLaR, revealed large differences in C5a receptor (C5aR) affinities between species. The antagonists bound to human, rat and dog PMNs with similar high affinities, but with lower affinities to PMNs from all other species. The C5a agonist also bound with varying affinities between species, but showed a different affinity profile to the antagonists. In contrast, recombinant human C5a had similar affinity for PMNs of all species investigated. The low correlation between the affinities of the antagonists and the agonist between species either suggests that different receptor residues are important for distinguishing between agonist/antagonist binding, or that the agonist and antagonist peptides bind to two distinct sites within the C5aR.

Phaeochromocytoma diagnosed during labour.

The diagnosis of phaeochromocytoma during pregnancy is rare. We present the management of vaginal delivery in a woman diagnosed with the condition during labour. A Medline search and follow-up of references failed to find any similar report in the last 30 years.

Autoantibodies to acetylcholinesterase revisited.

A sensitive and specific enzyme linked immunosorbent assay (ELISA) utilizing human recombinant acetylcholinesterase has been employed for the detection of human antibodies to human acetylcholinesterase. The method can detect allogenic antibodies to the Yt(a) form of human erythrocyte AChE. Adaptation of this ELISA method allowed the IgG subclass typing of IgG anti-AChE antibodies, which could help to determine the possible role of these antibodies in the aetiology of any neurological conditions. Routine serological investigations established the AChE phenotype of each of the patients recruited, to determine whether anti-AChE antibodies were allogenic or autogenic in origin. These techniques were used to determine the incidence of autoantibodies to AChE in patients with neurological conditions, including the subtypes of motor neuron disease. The data presented are not consistent with earlier reports of a high incidence of autoantibodies to AChE in amyotrophic lateral sclerosis and progressive muscular atrophy.

A new small molecule C5a receptor antagonist inhibits the reverse-passive Arthus reaction and endotoxic shock in rats.

C5a is implicated as a pathogenic factor in a wide range of immunoinflammatory diseases, including sepsis and immune complex disease. Agents that antagonize the effects of C5a could be useful in these diseases. We have developed some novel C5a antagonists and have determined the acute anti-inflammatory properties of a new small molecule C5a receptor antagonist against C5a- and LPS-induced neutrophil adhesion and cytokine expression, as well as against some hallmarks of the reverse Arthus reaction in rats. We found that a single i.v. dose (1 mg/kg) of this antagonist inhibited both C5a- and LPS-induced neutropenia and elevated levels of circulating TNF-alpha, as well as polymorphonuclear leukocyte migration, increased TNF-alpha levels and vascular leakage at the site of immune complex deposition. These results indicate potent anti-inflammatory activities of a new C5a receptor antagonist and provide more evidence for a key early role for C5a in sepsis and the reverse Arthus reaction. The results support a role for antagonists of C5a receptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease.

Randomized placebo-controlled trial to assess the effect of remifentanil and propofol on bispectral index and sedation.

The effect of the combination of opiates and hypnotics on bispectral index (BIS) is unclear. This double-blind placebo-controlled trial investigated the effect on BIS and sedation of different infusion doses of remifentanil combined with a steady infusion of propofol. Forty patients initially received a target-controlled infusion of propofol 2 micrograms ml-1 for 15 min. They were then randomized to receive either placebo, 0.01, 0.05 or 0.1 microgram kg-1 min-1 remifentanil for a further 15 min. We found a significant correlation between the dose of remifentanil and the change of BIS after 15 min of infusion. The correlation between all the sedation scores and their corresponding BIS was also significant. We concluded that remifentanil, in combination with propofol, reduces BIS when used for sedation.

The hormonal response to a d-fenfluramine challenge in trained and sedentary men.

PURPOSE: The purpose of the present study was to examine the responsiveness of serotonergic receptors in endurance trained and sedentary men. METHODS: The serum prolactin and cortisol responses to the oral administration of 30 mg of the serotonin releaser and reuptake inhibitor d-fenfluramine were determined in eight male endurance-trained subjects and seven male sedentary controls. RESULTS: A Friedman's repeated-measures test for both the endurance-trained (P = 0.006) and sedentary (P = 0.018) prolactin results demonstrated a change in the mean prolactin concentration over time, but no difference in prolactin response was observed between the subject groups (P = 0.81). In both subject groups, the serum cortisol concentration remained unchanged. However, the mean serum concentration of cortisol for the endurance-trained subjects at each time point tended to be lower than at the corresponding time point for the sedentary subject group and was significantly lower at 180 min (P = 0.04). CONCLUSION: The present study suggests that, in contrast to an earlier report of down-regulation of 5-HT1A receptor function in endurance-trained subjects in response to a nonspecific challenge, postsynaptic 5-HT2 function as determined by the d-fenfluramine-evoked alteration in the plasma concentration of prolactin is not altered by endurance training.

Platelet serotonin transporter density and related parameters in endurance-trained and sedentary male subjects.

A number of peripheral indices of serotonergic function were examined in endurance-trained (ET) and sedentary males using the blood platelet as a model of the serotonergic neurone. The aim of the study was to investigate possible involvement and adaptation of the central serotonergic system in exercise-induced fatigue. The [3H] paroxetine-defined density of platelet serotonin transporters, platelet serotonin content and the plasma concentration of amino acids were determined in 10 ET and eight sedentary males. The mean (standard deviation) density of the serotonin transporter in the platelet membranes of the ET subjects was greater [1237 (182) fmol mg protein-1] than that of the sedentary subjects [910 (119) fmol mg protein-1; P = 0.013]. No difference (P = 0.51) could be seen between the median (range) platelet serotonin content of the ET subjects [0.98 (0.37-3.04) nmol platelet-10] and that of the sedentary subjects [0.82 (0.18-1.49) nmol platelet-10]. The platelet poor plasma concentrations of tryptophan and tyrosine were lower in the ET subjects (P = 0.028 and 0.015, respectively). The present study suggests that the platelet membrane of the ET subjects has a greater density of the serotonin transporter and that this is inversely related to the circulating concentration of the serotonin precursor, tryptophan. It remains to be resolved whether the increase in serotonin transporter density in the platelet membrane of ET subjects is reflected centrally and whether the ET platelet population may be sufficiently different from that of sedentary individuals to alter serotonin transporter density.

Ether in an isoflurane vaporizer and the use of vapour analysers in safe anaesthesia.

A Penlon Sigma isoflurane vaporizer was found to contain some diethyl ether. This had escaped from a ruptured temperature compensation device within the vaporizer. The Datex AS/3 vapour analyser detected the foreign agent and displayed a warning. Different types of vaporizer compensation devices are highlighted and the use of vapour analysers is discussed. We conclude that these analysers are invaluable for indicating that the patient is receiving the correct concentration of an inhalation agent but are of little use in the detection of all but a few possible contaminants.

Smoking impairs the activity of endothelial nitric oxide synthase in saphenous vein.

Smoking impairs the endothelium-dependent relaxation of arteries and veins, with the maximum relaxation in response to the calcium ionophore A23187 of saphenous vein rings being reduced from 53 +/- 4% in nonsmokers to 27 +/- 5% in smokers. We have investigated whether this endothelial dysfunction was attributable to altered activity or concentration of nitric oxide synthase (NOS). The concentration of NOS in saphenous vein endothelium, determined by Western blotting and immunohistochemistry, was not different in nonsmokers and smokers. Nitrite production from vein strips stimulated with A23187 was higher in nonsmokers (median 23.6 nmol.cm-2.h-1) than smokers (median 3.3 nmol.cm-2.h-1), P=.001, this difference being abolished when vein strips were preincubated in the presence of NG-monomethyl-L-arginine. Organ chamber studies to monitor the endothelium-dependent relaxation of vein rings in response to A23187 showed that preincubation of rings from smokers with either L-arginine (3mmol/L) or superoxide dismutase (250 U/mL) did not improve the maximum relaxation. In contrast, preincubation of vein rings from smokers with 20 micromol/L tetrahydrobiopterin increased the maximum relaxation from 27 +/- 5% to 51 +/- 6%, P=.01. Preincubation of vein from smokers with tetrahydrobiopterin also significantly increased nitrite and cGMP production in response to stimulation with A23187. The impaired endothelium-dependent relaxation of saphenous vein rings from smokers appears to be caused by a reduction in the activity of endothelial NOS that is attributable to an inadequate supply of the coenzyme tetrahydrobiopterin.