Ablation, flux, and atmospheric implications of meteors inferred from stratospheric aerosol.

Single-particle analyses of stratospheric aerosol show that about half of the particles contain 0.5 to 1.0 weight percent meteoritic iron by mass, requiring a total extraterrestrial influx of 8 to 38 gigagrams per year. The sodium/iron ratio in these stratospheric particles is higher and the magnesium/iron and calcium/iron ratios are lower than in chondritic meteorites, implying that the fraction of material that is ablated must lie at the low end of previous estimates and that the extraterrestrial component that resides in the mesosphere and stratosphere is not of chondritic composition.

Hypertonic citrate solution as an alternative to modified Euro-Collins' solution for lung preservation.

In a canine model of acute ischemic lung injury, a hypertonic citrate solution (HTC) widely used for renal preservation in the United Kingdom, was compared with modified Euro-Collins' solution (ECS) currently the most widely clinically used pulmonary perfusate. Ten beagle dogs underwent left thoracotomy and exclusion of the left lung in situ. The lung was flushed with 30 ml/kg of either HTC or ECS and subjected to 60 min of warm ischemia. The circulation to the lung was then restored, the contralateral lung excluded, and the animal ventilated at a fixed FiO2 of 0.4 for 4 hr. Lung function was assessed by arterial oxygenation and hemodynamic measurements and, following sacrifice, by lung weight gain, bronchoalveolar lavage, and ultrastructural studies. Flush perfusion with HTC was associated with significantly less severe reperfusion injury, as determined by superior arterial oxygenation (PaO2 at 1 hr: HTC--152 mmHg [(95% confidence interval) CI] [122-182], ECS--59 [47-70]; PaO2 at 4 hr: HTC--124 [100-149], ECS--51 [42-61]), lower pulmonary vascular resistance index (PVRI at 4 hrs: HTC--838 dynes sec cm-5m-2 [651-1075], ECS--1233 [963-1588]); and lower lung weight (HTC--85 g [66-107], ECS--146 [114-184]). Bronchoalveolar lavage studies demonstrated an influx of neutrophils following reperfusion that was significantly less marked in the HTC group (increase in % neutrophils: HTC 24 [19-29], ECS 77 [72-82]). Lung injury assessed by electron microscopy tended to be less severe in the HTC animals. We conclude that HTC may offer an alternative superior to ECS for lung preservation.

Amelioration of lung ischemic injury with prostacyclin.

The single-flush technique of lung preservation is thought to be enhanced by prostaglandin treatment. In order to test this hypothesis, ten beagle dogs underwent thoracotomy and in situ flush perfusion of the excluded left lung with 30 ml/kg of cold, modified Euro-Collins' solution. Group 1 (n = 5) received pretreatment with 30 ng/kg/min of PGI2 by infusion and as an additive to the flush (20 micrograms/L). Group 2 (n = 5) received no PGI2 and served as controls. Following 60 min of warm ischemia, the left lung was reperfused, the contralateral lung excluded, and the animal ventilated at a fixed FiO2 of 0.4 for 4 hr. The severity of reperfusion injury was assessed by arterial oxygenation and hemodynamic measurements and, following sacrifice, by lung weight gain and bronchoalveolar lavage and ultrastructural studies. PGI2 therapy resulted in significant amelioration of reperfusion injury, with superior oxygenation at both 1 and 4 hr (PaO2 at 1 and 4 hr, respectively; PGI2: 145 mmHg +/- 17.0 and 114 +/- 11.2; no PGI2: 59 mmHg +/- 5.8 and 51 +/- 4.5; P less than 0.01 at both times), lower pulmonary vascular resistance index at 4 hr (PVRI; PGI2: 913 dynes sec cm-5m-2 +/- 91; no PGI2: 1239 +/- 68; P less than 0.05) and lower lung weight (PGI2: 76 g +/- 4; no PGI2: 146 +/- 10; P less than 0.001). Bronchoalveolar lavage studies revealed an influx of neutrophils following reperfusion that was less marked in the PGI2 group (increase in % neutrophils; PGI2: 50.4 +/- 6.7; no PGI2: 76.9 +/- 6.0; P less than 0.05). Lung injury score assessed by electron microscopy was lower in the PGI2 group (PGI2: 5.2 +/- 1.1; no PGI2; 8.1 +/- 0.5; P less than 0.05). It is concluded that PGI2 treatment is protective against ischemic lung injury in this model.

Inhibition of immediate hypersensitivity reactions in laboratory animals by a phenanthroline salt (ICI 74,917).

1. The activity of a new anti-allergic compound, I.C.I. 74,917, has been studied in the rat, mouse and guinea-pig. 2. Following intravenous administration, I.C.I. 74,917 inhibits in a dose-dependent manner passive cutaneous anaphylaxis induced in rats and mice by heat-labile homocytotropic antibody. In rats, its potency is approximately 300 times that of disodium cromoglycate. 3. To achieve maximal inhibition, it is necessary to administer I.C.I. 74,917 at the same time as antigenic challenge; dosing before or after challenge has much less effect. 4. Liberation of histamine, provoked by the antigenic challenge of mast cells passively sensitized in vitro by IgE-like antibody, is reduced in the presence of I.C.I. 74,917. 5. Intravenous administration of the compound has no significant effect upon local blueing reactions provoked in the rat by intradermal injection of histamine, 5-hydroxytryptamine or Compound 48/80. It has only a slight effect at high doses upon passive cutaneous anaphylaxis induced in the rat by heat-stable homocytotropic or heterologous (guinea-pig) antibodies. 6. Although not a bronchodilator in the guinea-pig, I.C.I. 74,917 partially inhibits systemic anaphylaxis. A consistent reduction in the severity of antigen-induced bronchospasm was demonstrated in the Konzett-Rossler preparation at doses comparable to those inhibiting passive cutaneous anaphylaxis in the rat. However, there was only slight inhibition of passive cutaneous anaphylaxis in the guinea-pig. 7. I.C.I. 74,917 itself induces bronchospasm when administered to anaesthetized guinea-pigs or to a guinea-pig isolated lung preparation. This effect is reversed by salbutamol, but is not prevented by the prior administration of mepyramine, atropine or methysergide. 8. These results indicate that in the rat, mouse and guinea-pig, I.C.I. 74,917 is a potent inhibitor of certain types of immediate hypersensitivity reactions.

Inhibition of contact sensitivity in the mouse by topical application of corticosteroids.

1. Topical application of oxazolone to the ears of mice previously sensitized to this hapten resulted in a marked increase in ear weight 24 h later.2. Topical application of hydrocortisone, betamethasone 17-valerate, fluocinolone acetonide or triamcinolone acetonide inhibited this response in a dose dependent manner.3. The free alcohols of the three fluorinated compounds were only weakly active.4. Activity in this model was truly local. Oral administration of hydrocortisone or fluocinolone acetonide at doses comparable to those used topically failed to inhibit the ear swelling.5. Some steroids with poor anti-inflammatory properties had no significant effect.

Comparison of the effects of xamoterol and isoprenaline on rat cardiac beta-adrenoceptors: studies of function and regulation.

1. The effects of the beta 1-selective partial agonist xamoterol and the full agonist isoprenaline on rat cardiac beta-adrenoceptors were compared in functional studies of heart rate response in vivo and in vitro. In addition, the ability of both agents to cause receptor down-regulation in the rat heart following chronic (6 days) subcutaneous infusions was assessed by radioligand binding with [125I]-pindolol. 2. In the functional studies, xamoterol produced a maximal effect equivalent to approximately 65% of that of isoprenaline and was overall less potent than the full agonist. 3. Compared to saline control, the density of beta-adrenoceptors was reduced approximately 39% in ventricular membranes prepared from animals after 6 days of isoprenaline infusion but was unaffected by xamoterol. The relative proportions of the beta-adrenoceptor subtypes were unchanged by either active treatment. 4. Plasma xamoterol level at the end of the infusion period was equivalent to that associated with maximum tachycardia in vivo and to the concentration producing maximal stimulation of the rat isolated atrium in vitro. Thus suggesting 100% beta-adrenoceptor occupancy during the period of xamoterol infusion. 5. These results indicate that in this animal model xamoterol does not induce cardiac beta-adrenoceptor down-regulation during chronic treatment, with doses that produce a maximal functional response both in vitro and in vivo.

Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy]-pen tane (AMG-126737).

Emerging evidence suggests that mast cell tryptase is a therapeutic target for the treatment of asthma. The effects of this serine protease are associated with both pathophysiologic pulmonary responses and pathologic changes of the asthmatic airway. In this study, the tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-p henoxy]-pentane (AMG-126737) was evaluated for its pharmacologic effects against allergen-induced airway responses. AMG-126737 is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater than 10- to 200-fold selectivity versus other serine proteases. Intratracheal administration of AMG-126737 inhibited the development of airway hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015 mg/kg. In addition, the compound exhibited oral activity in the guinea pig model. The in vivo activity of AMG-126737 was confirmed in a sheep model of allergen-induced airway responses, where the compound inhibited early and late phase bronchoconstriction responses and the development of airway hyperresponsiveness. These results support the proposed role of tryptase in the pathology of asthma and suggest that AMG-126737 has potential therapeutic utility in this pulmonary disorder.

Mitral valve replacement combined with coronary artery operation: determinants of early and late results.

Mitral valve replacement combined with coronary artery bypass grafting has been reported as being associated with a higher mortality than either mitral valve replacement or coronary artery bypass grafting alone. Cause of mitral valve disease and severity of mitral regurgitation have been reported as related to mortality. To study the correlation of the cause of mitral valve disease and severity of mitral regurgitation to hospital mortality and long-term survival, we analyzed the results of 135 patients undergoing mitral valve replacement and coronary artery bypass grafting between June 1974 and August 1989. The hospital mortality was 11.8% (16/135). Fifteen preoperative and operative variables were tested for correlation with hospital or late mortality using univariate tests and multivariate regression. Advanced age (greater than 60 years), New York Heart Association functional class, and wall motion score were independently associated with hospital mortality (p less than 0.05). The cause of mitral valve disease and severity of mitral regurgitation were not related to hospital mortality or long-term survival (p greater than 0.05). The follow-up rate was 96.6% for the hospital survivors (115/119). Mean follow-up was 52.6 +/- 4.1 months. There were 35 late deaths. Survival was 91.9%, 89.9%, 78%, and 49.9% at 1, 2, 5, and 10 postoperative years, respectively. Preoperative New York Heart Association functional class and use of catecholamines during the postoperative intensive care period were independently related to late survival (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Noninvasive 3-D ultrasound of atherosclerotic plaques in the Watanabe rabbit.

We have investigated the ability to quantitate atherosclerosis in the aortic arch of the Watanabe rabbit using noninvasive 3-D ultrasound. Our methodology utilizes postprocessing of videotaped freehand 2-D interrogations to form a compound 3-D data block. Structures may then be segmented on the attributed grey-scale level and volumes measured. Analysis of 3-D reconstructions revealed a low echo structure in the aortic arch of atherosclerotic rabbits, absent in nonatherosclerotic rabbits, at recognized sites of plaque predilection. This structure volume correlated closely with fatty streak volume determined from histology (r = 0.890). During a 30-week study, this structure volume increased in untreated animals, but was blocked by treatment with the antiatherosclerotic agent probucol. Thus, a new 3-D ultrasound methodology has been used noninvasively to detect and quantitate a low echo structure corresponding to fatty streaks in the Watanabe rabbit aortic arch. This new methodology could potentially aid plaque burden quantification in human peripheral arteries.

Three-dimensional freehand ultrasound: image reconstruction and volume analysis.

A system is described that rapidly produces a regular 3-dimensional (3-D) data block suitable for processing by conventional image analysis and volume measurement software. The system uses electromagnetic spatial location of 2-dimensional (2-D) freehand-scanned ultrasound B-mode images, custom-built signal-conditioning hardware, UNIX-based computer processing and an efficient 3-D reconstruction algorithm. Utilisation of images from multiple angles of insonation, "compounding," reduces speckle contrast, improves structure coherence within the reconstructed grey-scale image and enhances the ability to detect structure boundaries and to segment and quantify features. Volume measurements using a series of water-filled latex and cylindrical foam rubber phantoms with volumes down to 0.7 mL show that a high degree of accuracy, precision and reproducibility can be obtained. Extension of the technique to handle in vivo data sets by allowing physiological criteria to be taken into account in selecting the images used for construction is also illustrated.

Comparison of selected measures of field dependence.

An examination was made to determine the extent to which the Flexibility of Closure subtest from Hakstian and Cattell's Comprehensive Ability Battery could be substituted for Witkin's Rod-and-frame Test of field dependency. Although the data for 48 subjects (aged 11 to 17 yr.) yielded a significant zero-order correlation between the two tests for females, it was judged insufficient to warrant substitution of the former for the latter test.

Laser-induced ion formation thresholds of aerosol particles in a vacuum.

Using a time-of-flight mass spectrometer, we have measured the threshold for producing ions from various aerosol particles in avacuum with laser radiation at 248 nm,308 nm, and 10.6µm. In addition, a limited amount of similar data were taken at 193 and 337 nm. At 10.6 µm, two thresholds were observed: one near 3 GW/cm(2), which corresponds to partial ionization, and another at 6 GW/cm(2), which we attribute to plasma formation. At 308 nm, the threshold for ion production is on the order of 200 MW/cm(2). Shorter wavelengths require even less energy, with < 100 MW/cm(2) yielding normal molecular-mass spectra and approximately 500 MW/cm(2) fragmenting the sample to atomic ions.

The mechansim of tachyphylaxis to ICI 74,917 and disodium cromoglycate.

Pre-incubation in vitro of sensitised peritoneal mast cells for 10 min with either ICI 74,917 (10-5 M) abolished the ability of either drug to inhibit histamine release when subsequently presented to the cells at the same time as antigen. In the case of disodium cromoglycate, tachyphylaxis was abolished by washing the cells after pre-incubation with the drug. The failure to abolish tachyphylaxis to ICI 74,917 was due to the high pre-incubation concentration employed, as at lower concentrations (10-8 M) tachyphylaxis to ICI 74917 was readily abolished by washing. Tachyphylaxis to these anti-allergic agents may be related to a physical blocking of drug receptor sites on or in mast cells.

Inhibition of immediate hypersensitivity reactions in the rat by ICI 74,917 and disodium cromoglycate.

ICI 74,917, a potent inhibitor of IgE-mediated passive cutaneous anaphylaxis (PCA) in the rat, exhibited tachyphylaxis in that pre-dosing sensitised rats with a high dose of compound reduced the inhibitory effect on rat PCA of a second dose given at challenge. This phenomenon was most apparent when the pre-dose-challenge dose interval was 15--60 min. Similar findings were obtained using antigen-induced histamine release in vitro from rat peritoneal cells. In these respects, ICI 74,917 was similar to disodium cromoglycate (DSCG) although DSCG appeared less effective in inducing tachyphylaxis than ICI 74,917. There was no evidence in vivo or in vitro that a high dose of either DSCG or ICI 74,917 enhanced the activity of a second low dose of either drug given at challenge.

Conformation of methyl beta-lactoside bound to the ricin B-chain: interpretation of transferred nuclear Overhauser effects facilitated by spin simulation and selective deuteration.

Spin simulation and selective deuteration have been used to aid in the interpretation of 1D transferred nuclear Overhauser effect (TRNOE) NMR experiments on ricin B-chain/ligand systems. Application of these methods has revealed a change in the conformation of deuterated methyl beta-lactoside upon binding to the ricin B-chain which results in a slight change in glycosidic torsional angels which appear to dominate in the solution conformation. The combination of simulation and experiment also shows an important sensitivity of TRNOE magnitudes to dissociation rate constants and available spin-diffusion pathways for the ricin B-chain/ligand systems under study. The sensitivity to dissociation rates allows determination of rate constants for methyl beta-lactoside and methyl beta-galactoside of 50 and 300 s-1, respectively.