Measurements of the concentration and composition of nuclei for cirrus formation.

This article addresses the need for new data on indirect effects of natural and anthropogenic aerosol particles on atmospheric ice clouds. Simultaneous measurements of the concentration and composition of tropospheric aerosol particles capable of initiating ice in cold (cirrus) clouds are reported. Measurements support that cirrus formation occurs both by heterogeneous nucleation by insoluble particles and homogeneous (spontaneous) freezing of particles containing solutions. Heterogeneous ice nuclei concentrations in the cirrus regime depend on temperature, relative humidity, and the concentrations and physical and chemical properties of aerosol particles. The cirrus-active concentrations of heterogeneous nuclei measured in November over the western U.S. were <0.03 cm-3. Considering previous modeling studies, this result suggests a predominant potential impact of these nuclei on cirrus formed by slow, large-scale lifting or small cooling rates, including subvisual cirrus. The most common heterogeneous ice nuclei were identified as relatively pure mineral dusts and metallic particles, some of which may have origin through anthropogenic processes. Homogeneous freezing of large numbers of particles was detected above a critical relative humidity along with a simultaneous transition in nuclei composition toward that of the sulfate-dominated total aerosol population. The temperature and humidity conditions of the homogeneous nucleation transition were reasonably consistent with expectations based on previous theoretical and laboratory studies but were highly variable. The strong presence of certain organic pollutants was particularly noted to be associated with impedance of homogeneous freezing.

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.

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.

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.

Potent selective nonpeptidic inhibitors of human lung tryptase.

Human lung tryptase, a homotetrameric serine protease unique to mast cell secretory granules, has been implicated in the pathogenesis of asthma. A hypothesis that tethered symmetrical inhibitors might bridge two adjacent active sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure-activity relationship against human tryptase with one series possessing subnanomolar potencies. Additional evidence supporting the concept of active-site bridging is also presented.

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.

Video-assisted thoracoscopy.

Recent advances in video-imaging and minimally invasive surgical instrumentation have expanded the role of thoracoscopy in the diagnosis and treatment of intrathoracic conditions. This prospective study describes the use of video-assisted thoracoscopy (VAT) in 100 consecutive patients. There were 70 males and 30 females with a mean age of 54.6. They underwent 103 VAT procedures with 41 thoracoscopic biopsies of lung, pleural, chest wall and mediastinal abnormalities, 32 for treatment of recurrent or persistent pneumothorax, 18 for thoracoscopic assessment of pulmonary and pleural tumours and 12 for thoracoscopic resection of peripheral lung lesions, chest wall, mediastinal and pleural tumours. Eighty-one patients had VAT procedures alone while the remaining 19 had VAT proceeding to thoracotomy. The mean operating time for VAT alone was 51 min (range 30-135 min). There were no operative deaths. There were 8 significant complications from which patients recovered fully. Patients who underwent VAT alone were shown to have earlier postoperative mobilization, reduction in parenteral analgesic requirement and reduced length of hospital stay compared to patients undergoing additional thoracotomy. A telephone survey of patients on returning home showed that patients undergoing VAT alone returned to full activity earlier than those who had thoracotomy (mean 9.0 vs mean 19.4 days). This study confirms that VAT is a safe and effective procedure in the management of pulmonary, mediastinal and pleural disease and the treatment of persistent and recurrent pneumothorax. Its role in the resection of pulmonary malignancy remains to be defined.

Predominant alpha 1-adrenoceptor-mediated contraction in the human internal mammary artery.

alpha-Adrenoceptor agonists and antagonists are widely used perioperatively for internal mammary artery (IMA)-coronary artery bypass operations. To determine subtypes of alpha-adrenoceptors in the human IMA, we studied responses of isolated human IMA segments to alpha-adrenoceptor agonists, antagonists, and electrical stimulation in organ baths. The IMA ring segments (3 mm long) were set up at a physiologic and comparable condition according to their own length-tension curves. alpha 1-Agonist methoxamine (MO) induced 2.65 +/- 0.70 g force and alpha 1, alpha 2-agonist norepinephrine (NE) induced 4.07 +/- 0.70 g force. The contractions induced by both MO and NE were totally abolished by alpha 1-antagonist prazosin (0.1 microM) but not alpha 2-antagonist yohimbine. alpha 2-Agonist UK14304 induced only 0.39 +/- 0.17 g force, which was significantly less than that induced by MO or NE (p < 0.001). Contractions induced by electrical field stimulation (2, 10, 20 Hz) were decreased by alpha 1-antagonist prazosin 1 microM (p < 0.01) but potentiated by alpha 2-antagonist yohimbine. These results strongly suggest that in the human IMA the postjunctional alpha-adrenoceptors are predominantly of the alpha 1-subtype and therefore the alpha-adrenoceptor agonist-induced contraction and the sympathetic nerve stimulation-induced contraction is mediated mainly by activation of the alpha 1-adrenoceptors.

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.

Computer modelling of glycolipids at membrane surfaces.

Interactions of membrane anchored molecules such as glycolipids with a membrane surface are important in determining headgroup conformation. It is therefore essential to represent these membrane surface interactions in molecular modeling studies of glycolipids and other membrane bound molecules. We introduce here an energy term that represents the interaction of molecules with a membrane bilayer. This membrane interaction energy term has been added to the potential energy function of a molecular dynamics and mechanics program and has been parameterized using partition coefficients between an aqueous solution and a vesicular membrane for two model glycolipids.

The aminoquinazoline group as a replacement for the salicylamide group: the design and synthesis of a novel highly selective beta 1 adrenoceptor partial agonist.

The high potency at beta 1 receptors, excellent selectivity (beta 1/beta 2) and high degree of agonism displayed by compounds such as 1 is believed to be due in part to the salicylamide side chain. Two conformations of salicylamide are known to exist in the crystal state (2 and 3), but ab initio calculations suggest that in the absence of crystal packing forces 2 should be more stable. The aminoquinazoline group was judged to be a good replacement for salicylamide in 1, and consequently the oxypropanolamine derivative 4 was prepared. 4 shows extremely high potency at the beta 1 receptor, and excellent beta 1/beta 2 selectivity. It has comparable in vitro activity to 1, although it displays a lower degree of agonism. These results suggest that in this system aminoquinazoline appears to be an excellent mimic of the salicylamide group.

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)

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.

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.

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.

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.

Selecting the optimal dose of low-molecular-weight hydroxyethyl starch (Pentastarch) for granulocyte collection.

A new, rapidly excreted, low-molecular-weight form of hydroxyethyl starch (Pentastarch), is effective and safe in centrifugation leukapheresis. To define the optimal dose of Pentastarch, 12 subjects donated granulocytes by continuous-flow, centrifugation leukapheresis on three occasions at 3-week intervals. Each subject received approximately 250,500, or 1000 ml of Pentastarch according to a random sequence during procedures in which 81 of donor blood was consistently processed. Plasma Pentastarch concentrations (mean mg/ml) measured immediately after leukapheresis were 3.1, 6.7, and 12.7 for the 250, 500-, and 1000-ml doses, respectively. Total leukocyte and neutrophil yields with the 500- or the 1000-ml doses of Pentastarch were similar, and both were significantly greater (p less than 0.05) than those with the 250-ml dose. Neutrophil yields per concentrate (mean X 10(-10) were 0.74, 1.72, and 1.73 for the 250-, 500-, and 1000-ml doses, respectively. Pentastarch dose had little effect on lymphocyte and platelet yields. No serious adverse effects were evident for any dose of Pentastarch during 12 weeks of observation. In particular, the 1000-ml dose did not produce increased toxicity. Thus, a single 500-ml bottle of 10 percent Pentastarch produced maximal yields; efficacy was not improved by doubling the dose.