Acute pulmonary toxicity of urban particulate matter and ozone

We have investigated the acute lung toxicity of urban particulate matter in interaction with ozone. Rats were exposed for 4 hours to clean air, ozone (0.8 ppm), the urban dust EHC-93 (5 mg/m3 or 50 mg/m3), or ozone in combination with urban dust. The animals were returned to clean air for 32 hours and then injected (intraperitoneally) with [3H]thymidine to label proliferating cells and killed after 90 minutes. The lungs were fixed by inflation, embedded in glycol methacrylate, and processed for light microscopy autoradiography. Cell labeling was low in bronchioles (0.14 +/- 0.04%) and parenchyma (0.13 +/- 0.02%) of air control animals. Inhalation of EHC-93 alone did not induce cell labeling. Ozone alone increased (P < 0.05) cell labeling (bronchioles, 0.42 +/- 0.16%; parenchyma, 0.57 +/- 0.21%), in line with an acute reparative cell proliferation. The effects of ozone were clearly potentiated by co-exposure with either the low (3.31 +/- 0.31%; 0.99 +/- 0.18%) or the high (4.45 +/- 0.51%; 1.47 +/- 0.18%) concentrations of urban dust (ozone X EHC-93, P < 0.05). Cellular changes were most notable in the epithelia of terminal bronchioles and alveolar ducts and did not distribute to the distal parenchyma. Enhanced DNA synthesis indicates that particulate matter from ambient air can exacerbate epithelial lesions in the lungs. This may extend beyond air pollutant interactions, such as to effects of inhaled particles in the lungs of compromised individuals.     

Regional deposition and retention of particles in shallow, inhaled boluses: effect of lung volume

We evaluated the effects of volatile anesthetics on T-type calcium current (ICa,T) present in four different cell types using the whole cell version of the patch clamp technique. In dorsal root ganglion neurons and in two neuroendocrine cells--adrenal glomerulosa cells (AG) and thyroid C-cells--ICa,T was reversibly decreased by volatile anesthetics at clinically relevant concentrations, with isoflurane and enflurane being more potent that halothane. In AG cells, the most sensitive cell type tested, ICa,T was reduced 47%+/-4% (n = 6) by isoflurane (0.7 mM) and 56%+/-2% (n = 5) by enflurane (1.2 mM), but by only 24%+/-1% (n = 5; P < 0.05) by halothane (0.7 mM). Isoflurane caused a significant increase in the rate of deactivation of ICa,T in AG cells. In ventricular myocytes, however, ICa,T was much less sensitive to both isoflurane and halothane. The differential sensitivity of ICa,T in various cell types to the anesthetics may reflect differences in the channels expressed in these tissues or differences in the cellular intermediates involved in anesthetic action. Depression of ICa,T in neuronal cells may contribute to anesthetic action through decreases in cellular excitability. IMPLICATIONS: Using the patch clamp technique, we showed that T-type calcium channels, which promote cellular excitability, are inhibited by volatile anesthetics in neuronal and neuroendocrine cells, but not in ventricular myocytes. Inhibition of neuronal T-type channels may contribute to the mechanism of action of volatile anesthetics.     

Acute effects of ambient ozone on asthmatic, wheezy, and healthy children

Southern California children (10 to 12 years old) participated in a two-season study to assess the potential acute respiratory effects of ambient ozone (O3). Asthmatic (n = 49), wheezy (n = 53), and healthy (n = 93) children completed a four-day (Friday through Monday) study protocol, once in spring and again in summer, that included the use of daily activity and symptom diaries, heart rate recording devices, personal O3 samplers, and maximal effort spirometry several times per day. Data from regional monitoring stations were used to establish ambient hourly O3 concentrations. Analyses revealed that the children spent more time outdoors and were more physically active in the spring. Girls spent less time outdoors and were less physically active than boys. Personal O3 samplers correlated poorly with, and generally gave lower readings than, outdoor ambient monitors. Higher personal O3 exposures were associated generally with increased inhaler use, more outdoor time, and more physical activity. Children with asthma spent more time outdoors and were more active in the spring on high-O3 days (measured by personal sampler), and had the most trouble breathing, the most wheezing, and the most inhaler use on these days. Activity pattern data suggested that children with asthma protected themselves by being less physically active outdoors during the summer on high-O3 days. Wheezy children had the most trouble breathing during the summer on low-O3 days (measured by personal sampler). Observed relationships between O3 and pulmonary function were erratic and difficult to reconcile with existing knowledge about the acute respiratory effects of air pollution. We conclude that although asthmatic and wheezy children behave differently from their healthy peers with regard to symptoms and patterns of activity when challenged by ambient ozone, the nature of these changes remains inconsistent and ill-defined.     

Comparable potent coronary constrictor effects of endothelin-1 and big endothelin-1 in humans

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor produced from the precursor big ET-1 in endothelial cells. The coronary effects of these peptides in humans in vivo are unknown. Therefore, the effects of ET-1 and big ET-1 on coronary blood flow in relation to plasma ET-1 and big ET-1 levels were compared in healthy subjects. METHODS AND RESULTS: The peptides were infused intravenously at the rates of 0.2, 1, and 8 pmol/kg per minute. Each dose administered for 20 minutes except the highest dose of ET-1, which was administered for 10 minutes. ET-1 and big ET-1 evoked dose-related increases in mean arterial blood pressure from 93 +/- 4 to 107 +/- 4 mm Hg and from 89 +/- 2 to 122 +/- 5 mm Hg, respectively, at the highest dose. ET-1 and big ET-1 reduced coronary sinus blood flow, measured with thermodilution by a maximum of 25 +/- 4% and 28 +/- 8% and increased coronary vascular resistance by 50 +/- 9% and 107 +/- 26%, respectively. Coronary sinus, but not arterial, oxygen saturation was reduced in parallel with the coronary sinus blood flow. The effects of ET-1 and big ET-1 were similar at corresponding time points. During infusion of ET-1, a 19 +/- 5% extraction of ET-1 was observed over the coronary vascular bed (P < .05). Administration of big ET-1 elevated arterial plasma ET-1 levels by 2.4-fold, and after correction for the local extraction of ET-1, a myocardial production of ET-1 was observed. CONCLUSIONS: ET-1 and big ET-1 induce comparable increases in blood pressure and coronary constriction in humans in vivo. The results also suggest a net local removal of circulating ET-1 and big ET-1 and a local conversion of big ET-1 into ET-1 within the coronary vascular bed.     

Flow cytometric analysis of macrophage response to ceramic and polyethylene particles: effects of size, concentration, and composition

The aim of this work was to study the effect of a dose of 150 microCi 131I on the barrier properties of the thyroid epithelium in pregnant female rats. Thirty-five female Wistar rats were divided into a control and four experimental groups (each distinguished by the time of 131I injection: group I--no less then 12 days before mating; groups II, III, and IV--on 5th, 10th, and 16th days of gestation, respectively). The thyroid glands were fixed in Bouin's fluid, embedded in paraffin, and stained immunohistochemically for thyroglobulin and fibronectin. In group IV the appearance of follicles with fibronectin-positive colloid demonstrates the penetration of blood plasma into the follicular lumen. There are more fibronectin positive follicles in group III. Regardless of the nature of the follicles' contents, numerous thyrocytes with an intensive fibronectin positive reaction begin to appear in the follicles. In group II the number of fibronectin positive follicles and thyrocytes is clearly reduced, and in group I only a few remain. In group IV there is a noticeable reduction in the quantity of colloid inside the follicles and often an absence of any thyroglobulin positive reaction. There are thyrocytes in which thyroglobulin positive granules localized in the basal zone. There is thyroglobulin positive staining in the stroma and blood vessels. In group II thyroglobulin is no longer found in the stroma. Small doses of 131I provoke a serious breakdown in the thyroid epithelium's barrier properties, although these changes are of a transient nature. The central zone of the thyroid gland reacts more actively and dynamically to exposure to radioactive iodine than the peripheral zone.     

Increased concentrations of endothelin-1 messenger RNA in tissues and endothelin-1 peptide in plasma in septic pigs: modulation by betamethasone

OBJECTIVES: To study the expression of preproendothelin-1 messenger RNA (mRNA) in tissue after Escherichia coli lipopolysaccharide challenge and to evaluate the possible effects of betamethasone both regarding endothelin-1 production as well as hemodynamic and vascular effects during E. coli lipopolysaccharide infusion in pigs in vivo. DESIGN: Prospective trial. SETTING: Laboratory at a university medical center. SUBJECTS: Ten domestic pigs, weighing 18 to 25 kg. INTERVENTIONS: Anesthetized pigs were given continuous infusions of E. coli lipopolysaccharide (15 micrograms/kg/hr for 3 hrs), with or without prior treatment with betamethasone (0.5 mg/kg im 12 hrs before the start of the surgical preparation and 0.5/kg iv at the start of the preparation). MEASUREMENTS AND MAIN RESULTS: The E. coli lipopolysaccharide infusion evoked the characteristic cardiovascular changes observed in septic shock: decreased mean arterial pressure and cardiac output; increased heart rate and increased pulmonary vascular resistance. Large increases in both arterial plasma concentrations of endothelin-1-like immunoreactivity, as well as preproendothelin-1 mRNA concentrations in tissues, were also observed during the E. coli lipopolysaccharide infusion. Treatment with betamethasone significantly attenuated the E. coli lipopolysaccharide-induced increase in endothelin-1 plasma concentrations, whereas the increased mRNA concentrations were only slightly affected. Furthermore, betamethasone treatment also affected cardiovascular parameters, with significant attenuation of the E. coli lipopolysaccharide-induced increase in heart rate and a higher cardiac output after 60 mins of the E. coli lipopolysaccharide infusion. The urine production, which was markedly decreased during the E. coli lipopolysaccharide infusion, was significantly higher in the betamethasone-treated group compared with the control group. CONCLUSIONS: The present results indicate that the increased concentrations of endothelin-1-like immunoreactivity that are observed in septic shock may have negative effects on both cardiovascular parameters as well as renal function, which is in agreement with a possible role for endothelin-1 in the pathogenesis of septic shock.     

Elevated plasma endothelin-1 level in streptozotocin-induced diabetic rats and responsiveness of the mesenteric arterial bed to endothelin-1

Acute swimming stress destroyed the circadian rhythm of motility in rats. Bilateral electrolytic lesion of the dorsal hippocampus increased the night activity and resistance of animals to stress. Pinealectomy did not affect the circadian locomotion but increased rats' sensitivity to dysrhythmic stress effect.     

Relationship of inhaled ozone concentration to acute tracheobronchial epithelial injury, site-specific ozone dose, and glutathione depletion in rhesus monkeys

Acute pulmonary epithelial injury produced by short-term exposure to ozone varies by site within the tracheobronchial tree. To test whether this variability is related to the local dose of ozone at the tissue site or to local concentrations of glutathione, we exposed adult male rhesus monkeys for 2 h to filtered air or to 0.4 or 1.0 ppm ozone generated from 18O2. Following exposure, lungs were split into lobes and specimens were selected by microdissection so that measurements could be made on airway tissue of similar branching history, including trachea, proximal (generation one or two) and distal (generation six or seven) intrapulmonary bronchi, and proximal respiratory bronchioles. One half of the lung was lavaged for analysis of extracellular components. In monkeys exposed to filtered air, the concentration of reduced glutathione (GSH) varied throughout the airway tree, with the proximal intrapulmonary bronchus having the lowest concentration and the parenchyma having the highest concentration. Exposure to 1.0 ppm ozone significantly reduced GSH only in the respiratory bronchiole, whereas exposure to 0.4 ppm increased GSH only in the proximal intrapulmonary bronchus. Local ozone dose (measured as excess 18O) varied by as much as a factor of three in different airways of monkeys exposed to 1.0 ppm, with respiratory bronchioles having the highest concentration and the parenchyma the lowest concentration. In monkeys exposed to 0.4 ppm, the ozone dose was 60% to 70% less than in the same site in monkeys exposed to 1.0 ppm. Epithelial disruption was present to some degree in all airway sites, but not in the parenchyma, in animals exposed to 1.0 ppm ozone. The mass of mucous and ciliated cells decreased in all airways, and necrotic and inflammatory cells increased. At 0.4 ppm, epithelial injury was minimal, except in the respiratory bronchiole, where cell loss and necrosis occurred, and was 50% that found in monkeys exposed to 1.0 ppm ozone. We conclude that there is a close association between site-specific O3 dose, the degree of epithelial injury, and glutathione depletion at local sites in the tracheobronchial tree.     

Acute effects of an endothelin-1 receptor antagonist bosentan at different stages of heart failure in conscious dogs

Deamination of cytosine residues contributes to the appearance of uracil in DNA. Uracil DNA glycosylase (UDG) initiates uracil excision repair to safeguard the genomic integrity. To study the mechanism of uracil excision in mycobacteria (organisms with G+C rich genomes), we have purified UDG from Mycobacterium smegmatis by more than 3000-fold. The molecular mass of M. smegmatis UDG, as determined by SDS/PAGE, is approximately 25 kDa and it shows maximum activity at pH 8.0. The N-terminal sequence analysis shows that the initiating amino acid, formyl-methionine is cleaved from the mature protein. More interestingly, unlike Escherichia coli UDG, which forms a physiologically irreversible complex with the inhibitor protein Ugi, M. smegmatis UDG forms a dissociable complex with it. M. smegmatis UDG excises uracil from the 5'-terminal position of the 5'-phosphorylated substrates. However, its excision from the 3'-penultimate position is extremely poor. Similar to E. coli UDG, M. smegmatis UDG also uses pd(UN)p as its minimal substrate. However, in contrast to E. coli UDG, which excises uracil from different loop positions of tetraloop hairpin substrates with highly variable efficiencies, M. smegmatis UDG excises the same uracil residues with comparable efficiencies. Kinetic parameters (Km and Vmax) for uracil release from synthetic substrates suggest that M. smegmatis UDG is an efficient enzyme and better suited for molecular biology applications. We discuss the usefulness of the distinct biochemical properties of M. smegmatis UDG in the possible design of selective inhibitors against it.     

Minimal daily variations of plasma and urinary endothelin-1 in healthy subjects

The daily profiles of both the plasma level and the urinary excretion rate of endothelin-1 were examined in 13 healthy volunteers (9 males and 4 females, aged 22 +/- 1 [SEM]). Plasma endothelin-1 (PET) was measured after a one-hour recumbency every 6 hours at 8 a.m., 2 p.m., 8 p.m. and 2 a.m. and the urinary excretion rate of endothelin-1 (UET) was determined in the urine collected every 6 hours. PET was found to be quite stable throughout the day, being 1.57 +/- 0.25 pg/ml at 8 a.m., 1.88 +/- 0.21 at 2 p.m., 2.2 +/- 0.24 at 8 p.m. and 1.90 +/- 0.20 at 2 a.m. After a one-hour ambulation, PET showed no statistical difference. UET also remained unchanged for each 6-hour collecting period, measuring 4.61 +/- 0.69, 3.98 +/- 0.46, 4.63 +/- 0.73 and 3.42 +/- 0.49 ng/hr, respectively. The absence of any daily variations in either PET or UET thus suggests that apparently no specific considerations need be applied regarding the time of taking samples to measure the plasma and urinary endothelin-1.     

Color Doppler imaging and plasma levels of endothelin-1 in low-tension glaucoma

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelin cells There are reports in the literature that ET-1 plasma levels are raised in low tension glaucoma (LTG). ET-1 plasma concentration and Color Doppler Imaging (CDI) evaluation in ophthalmic and posterior ciliary arteries were measured in 15 LTG patients and in 15 healthy subjects. The blood flow index recorded for the ophthalmic artery in normal subjects was a PSV of 36.646 +/- 6.611 cm/sec with RI of 0.717 +/- 0.019 while in the LTG patients it was 32.961 +/- 3.045 cm/sec (p < 0.003) with RI of 0.789 +/- 0.018 (p < 0.001). For the posterior ciliary arteries in the same two groups, we obtained a PSV of 13.878 +/- 4.149 cm/sec vs 8.720 +/- 1.645 cm/sec (p < 0.001) and an RI of 0.679 +/- 0.039 vs 0.722 +/- 0.024 (p < 0.001). The plasma ET-1 level in normal subjects was 1.720 +/- 0.174 pg while in LTG patients it was 2.947 +/- 0.217 pg (p < 0.001). On the basis of our experience, we think that GON and the visual field damage found in LTG can be attributed to an alteration in the endothelial self-regulating sections and consequent vascular insufficiency, particularly pronounced in the posterior ciliary arteries which, since it is these that provide the blood supply to the optic nerve head, leads to irreversible functional damage.     

Purification and characterization of endothelin-1 degradation activity from porcine kidney

In order to identify the membrane-bound peptidase that is responsible for the degradation of endothelin (ET), an endothelin-1 (ET-1) degradation enzyme was solubilized from membrane fractions of porcine kidney with 1% Triton X-100, and subsequently purified by column chromatographies, i.e., diethylamino-Sepharose ion exchange, gel permeation, Con A Sepharose and hydroxyapatite chromatography. On DEAE-Toyopearl ion exchange column chromatography, the ET degradation enzyme and aminopeptidase were separated, but ET degradation enkephalinase activities were not separable. In order to separate ET degradation enzyme and enkephalinase, the active fractions were loaded on each of the column chromatographies: sephacryl S-200, Con A Sepharose or hydroxyapatite. The ET degradation activities were co-migrated with enkephalinase activities on all of the three chromatographies. In addition, the ET degradation activities were inhibited by thiorphan, phosphoramidon and EDTA, which are known to inhibit enkephalinase. These results suggest that ET degradation activity in the membrane fractions of the kidney is related to enkephalinase and may be involved in the degradation of ET-1 in vivo.     

Immunoreactive endothelin-1, endothelin-2 and big endothelin-1 in follicular fluids of women undergoing ovulation induction for in-vitro fertilization

Atlantic cod (Gadus morhua) transferrin cDNAs were isolated from a liver cDNA library using a cod transferrin-derived polymerase chain reaction product as a hybridization probe. The composite nucleotide sequence of two overlapping clones was 2223 bp in length excluding the poly(A) sequence and was equivalent to 87% of the 3' end of the Atlantic salmon transferrin cDNA sequence. Comparison of the deduced amino acid sequence of cod, salmon, Xenopus and several mammalian transferrins revealed that the two fish sequences are more similar with respect to their amino acid sequence and the position of additions/deletions than to other vertebrate transferrins. Conservation of the iron-binding domains and cysteine residues involved in disulphide bridges indicates that all transferrins share similar tertiary structure and support the hypothesis that extant vertebrate transferrin genes were derived from a gene duplication before the divergence of fish, frogs and mammals. Cod transferrin mRNA was detected in both brain and liver RNA and to a much lesser extent in RNA isolated from kidney and heart in contrast to salmon and several other vertebrates in which the transferrin gene is not expressed in brain.     

Expression of endothelin-1 and effects of an endothelin receptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model

BACKGROUND: Rapid increase of pulmonary vascular resistance (PVR) early after reperfusion remains a major issue in clinical lung transplantation. A potent vasoconstrictor peptide, endothelin- plays an important role in various pulmonary pathophysiologic conditions and might induce increased PVR. We investigated the expression and influence of endothelin-1, and the effects of an ETA and ETB nonselective endothelin receptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model. METHODS: Left single lung allotransplantation procedures were performed in three groups of animals. In group I (n=5) lungs were preserved for 12 hours; in group II (n=5) lungs were preserved for 18 hours; and in group III (n=6) lungs were also preserved for 18 hours, and TAK-044 (5 mg/kg) was administered just before reperfusion. All donor lungs were flushed and preserved with low-potassium dextran glucose solution at 4 degrees C. RESULTS: Six hours after reperfusion, arterial oxygen tension (mm Hg, inspired oxygen fraction=1.0) was 512.9+/-34.7 in group I, 152.4+/-46.7 in group II, and 509.6+/-29.0 in group III; PVR index (dyne x sec x cm(-5) x m2) was 1130+/-142 in group I, 1820+/-142 in group II, and 1287+/-191 in group III. Plasma endothelin-1 level was elevated significantly, and endothelin-1-like immunoreactivity was found in a variety of pulmonary vascular tissue and was seen less with immunohistochemical evaluation in group II in bronchial tissue. Conclusions: These results suggest that endothelin-1 is expressed as a result of ischemia-reperfusion injury and may worsen early graft function. TAK-044 is beneficial in protecting the graft from high pulmonary vascular resistance and pulmonary edema during the early posttransplantation stage.     

Immunohistochemical localization of endothelin-1, endothelin-3 and endothelin receptors in human pheochromocytoma and paraganglioma

Endothelin (ET) and its receptor system have been shown to exert various biological effects on different types of cells in addition to their well-known vasoconstrictor activity. Recently ET-1, ET-3 and the ETB receptor have been shown to play an important role in the development of neural crest-derived cells and, in this context, pheochromocytomas have been reported to harbor ET-1. Endothelin-3 or ET receptor subtypes, however, have not been examined in pheochromocytoma and paraganglioma so far. In the present study the immunohistochemical localization of ET-1/big ET-1, ET-3/big ET-3 and the ETA and ETB receptors were investigated to clarify the biological characteristics of these two tumors using 32 pheochromocytomas and 11 extra-adrenal paragangliomas. Endothelin-1/big ET-1 was detected in 19 pheochromocytomas (59%) and eight paragangliomas (72%), while ET-3/big ET-3 was detected in 10 pheochromocytomas (31%) and three paragangliomas (27%). The ETA receptor was found in 21 pheochromocytomas (66%) and in eight paragangliomas (73%), while the ETB receptor was found in 25 pheochromocytomas (78%) and in eight paragangliomas (73%). Normal adrenomedullary cells lacked each antigen examined. Endothelin-immunoreactive tumor cells were distributed focally or in a manner scattered, while receptor-immunostained tumor cells were distributed with a focal pattern for the ETA receptor and with a focal or diffuse pattern for the ETB receptor. Endothelin and its receptor coexisted in the same tumor in 21 of 28 ET-positive pheochromocytomas and in eight of 10 ET-positive paragangliomas. In addition, seven pheochromocytomas and two paragangliomas revealed positivity of the receptor(s) irrespective of the absence of ET-immunoreactivity. In conclusion, ET and its receptor are frequently and concomitantly expressed in the pheochromocytoma and paraganglioma. From the highly frequent expression of this system or the receptor(s), ET-receptor-mediated signal transduction of these tumors concerning growth and/or cell survival is expected, although definite biological significance of this ligand-receptor system in these tumors awaits further investigation.     

Role of thromboxane A2, endothelin-1 and endothelin-3 in rat nephrotoxic serum nephritis

To clarify the role of thromboxane A2 (TxA2), endothelin-1 (ET-1) and endothelin-3 (ET-3) in the progression of glomerular injury in accelerated nephrotoxic serum nephritis (NTN) in the rat, we studied the expression of ET-1 and ET-3 at the kidney by immunohistochemical method and examined the effect of a novel TxA2 receptor antagonist, S-1452. The S-1452-treated group showed significantly lowered 24-hr proteinuria and milder glomerular cell proliferation and lobulation than the non-treated group (NT group) on experimental day 10. There was no significant difference in the glomerular polymorphonuclear cell (PMN) exudation between the 2 groups. Immunofluorescent findings revealed that ET-1 and ET-3 were seen along the glomerular capillary wall and partly in the mesangial area in all rats of the NTN group. The degree and positive rate of ET-1 and ET-3 staining were significantly higher in the NTN group than in the S-1452 group. These findings suggest that TxA2 may be an important mediator in the development of NTN, and that TxA2 receptor antagonist may be useful for the reduction of glomerular injury in this type of nephritis. In addition, local production of ET may contribute to the development of this nephritis.     

Regional deposition of inhaled particles in human lungs: comparison between men and women

We measured detailed regional deposition patterns of inhaled particles in healthy adult male (n = 11; 25 +/- 4 yr of age) and female (n = 11; 25 +/- 3 yr of age) subjects by means of a serial bolus aerosol delivery technique for monodisperse fine [particle diameter (Dp) = 1 micron] and coarse aerosols (Dp = 3 and 5 micron). The bolus aerosol (40 ml half-width) was delivered to a specific volumetric depth (Vp) of the lung ranging from 100 to 500 ml with a 50-ml increment, and local deposition fraction (LDF) was assessed for each of the 10 local volumetric regions. In all subjects, the deposition distribution pattern was very uneven with respect to Vp, showing characteristic unimodal curves with respect to particle size and flow rate. However, the unevenness was more pronounced in women. LDF tended to be greater in all regions of the lung in women than in men for Dp = 1 micron. For Dp = 3 and 5 micron, LDF showed a marked enhancement in the shallow region of Vp 200 ml. Total lung deposition was comparable between men and women for fine particles but was consistently greater in women than men for coarse particles regardless of flow rates used: the difference ranged from 9 to 31% and was greater with higher flow rates (P < 0.05). The results indicate that 1) particle deposition characteristics differ between healthy men and women under controlled breathing conditions and 2) deposition in women is greater than that in men.     

Acute effects of cocaine on human brain activity and emotion

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.     

Plasma endothelin-1 levels during transient acute myocardial ischaemia in men: effects of coronary revascularization

The endothelium-derived peptide endothelin-1 (ET-1) was evaluated in 14 male patients [mean age 52.74 years (SEM 1.10)] affected by coronary artery disease during a bicycle electrocardiographic stress test and dipyridamole echocardiogram. Both tests were performed before and after coronary revascularization. Fourteen healthy male subjects served as controls [mean age 53.21 years (SEM 1.63)]. Baseline plasma endothelin-1 levels were higher (P < 0.0001) in ischaemic patients [1.81 pg mL-1 (0.15, n = 14)] than in control subjects [0.61 pg mL-1 (0.03, n = 14)], but did not increase with exercise in both groups. Similar results were obtained with dipyridamole infusion. Endothelin-1 levels significantly decreased after coronary revascularization [before: mean 1.81 pg mL-1 (SEM 0.15, n = 14); after: mean 1.16 pg mL-1 (SEM 0.11), P < 0.002], without changes in the peptide response to both tests. In conclusion, elevated plasma endothelin-1 concentrations were found in patients with stable angina compared with non-ischaemic subjects. No changes were observed during exercise or dipyridamole infusion in both groups. Coronary revascularization was followed by a significant decrease in plasma endothelin-1 levels.     

Acute and chronic effects of bilateral lung transplantation without cardiopulmonary bypass on the first transplanted lung

BACKGROUND: Bilateral lung transplantation (BLT) without cardiopulmonary bypass (CPB) may exacerbate reperfusion injury to the initially engrafted lung because of increases in pulmonary flow during implantation of the second graft. METHODS: In a retrospective review of 23 BLT patients, we hypothesized that BLT without CPB injures the first transplanted lung measured by acute and late graft dysfunction compared to the second transplanted lung. Of the 23 BLT, 19 underwent transplantation without CPB while 4 patients were placed on CPB secondary to hemodynamic instability. RESULTS: Acute graft function was assessed by radiographic scoring of lung quadrants (blinded radiologist; 0 = no infiltrate; 1 = infiltrate; maximum = 2 per lung) and by arterial/alveolar oxygen tension ratios (PaO2/ FiO2) ratios. Late graft function was evaluated by quantitative perfusion scan. Lung perfusion was graded as abnormal if less than 50% on the right or less than 45% on the left (Fisher's exact). Radiographic scores were not different between first and second implanted lungs at 1 and 24 hours, PaO2/FiO2 ratios at 1 and 24 hours were 273+/-26 and 312+/-23, respectively, and perfusion scans at 3 and 12 months revealed normal differential blood flow. CONCLUSIONS: These findings suggest no acute or chronic differences occur between the first or second transplanted lung completed without CPB.