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Clinical review: Exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome - where do we go from here?
DOI: 10.1186/cc11512
© BioMed Central Ltd 2012
Published: 22 November 2012
Acute lung injury and acute respiratory distress syndrome (ARDS) are characterised by severe hypoxemic respiratory failure and poor lung compliance. Despite advances in clinical management, morbidity and mortality remains high. Supportive measures including protective lung ventilation confer a survival advantage in patients with ARDS, but management is otherwise limited by the lack of effective pharmacological therapies. Surfactant dysfunction with quantitative and qualitative abnormalities of both phospholipids and proteins are characteristic of patients with ARDS. Exogenous surfactant replacement in animal models of ARDS and neonatal respiratory distress syndrome shows consistent improvements in gas exchange and survival. However, whilst some adult studies have shown improved oxygenation, no survival benefit has been demonstrated to date. This lack of clinical efficacy may be related to disease heterogeneity (where treatment responders may be obscured by nonresponders), limited understanding of surfactant biology in patients or an absence of therapeutic effect in this population. Crucially, the mechanism of lung injury in neonates is different from that in ARDS: surfactant inhibition by plasma constituents is a typical feature of ARDS, whereas the primary pathology in neonates is the deficiency of surfactant material due to reduced synthesis. Absence of phenotypic characterisation of patients, the lack of an ideal natural surfactant material with adequate surfactant proteins, coupled with uncertainty about optimal timing, dosing and delivery method are some of the limitations of published surfactant replacement clinical trials. Recent advances in stable isotope labelling of surfactant phospholipids coupled with analytical methods using electrospray ionisation mass spectrometry enable highly specific molecular assessment of phospholipid subclasses and synthetic rates that can be utilised for phenotypic characterisation and individualisation of exogenous surfactant replacement therapy. Exploring the clinical benefit of such an approach should be a priority for future ARDS research.
Acute respiratory distress syndrome (ARDS), first described by Ashbaugh and colleagues in 1967 [1], is a leading cause of morbidity and mortality in critically ill patients. Outside clinical trial settings, mortality still remains as high as 50% [2]. Diffuse alveolar damage is a typical histopathological feature of ARDS [3]. Three sequential pathological stages of exudation, cellular proliferation and fibrosis are commonly recognised. In the early exudative phase, alveolar epithelial and endothelial injury lead to the accumulation of protein-rich pulmonary oedema. This phase is followed by varying degrees of type II cell proliferation, accumulation of fibroblasts and myofibroblasts associated with collagen deposition in the extracellular matrix, and in some patients this leads to fibrosis [3]. The clinical consequences of the initial injury are refractory hypoxemia and poor lung compliance necessitating mechanical ventilatory support. The diagnostic criteria established by the American-European Consensus Conference in 1994 encompass simple physiological, laboratory and radiological variables [4] but are limited by low specificity and substantial interobserver variability [5, 6]. According to these criteria, ARDS is diagnosed by PaO2/FiO2 ratio ≤200 mmHg with bilateral infiltrates on chest radiograph in the absence of raised left atrial hypertension. Acute lung injury (ALI) is defined by the same criteria as ARDS, but with a lesser degree of hypoxemia (PaO2/FiO2 ≤300 mmHg) [4].
ARDS/ALI may result from both direct lung injury (for example, pneumonia, aspiration, drowning and toxic inhalation) and indirect lung injury (for example, sepsis, trauma, blood transfusion and pancreatitis) [3], causing significant phenotypic heterogeneity among patients. Variability in both patients and pathology may explain the disappointing results from many ARDS clinical trials. Indeed, some authors question whether it is reasonable to cohort such varied pathologies within a single unifying diagnostic syndrome [7]. An expert consensus panel has recently proposed a new diagnostic definition (Berlin Definition of ARDS) [8], which subgroups patients according to disease severity defined by the degree of hypoxemia: mild (PaO2/FiO2 ≤300 mmHg); moderate (PaO2/FiO2 ≤200 mmHg); and severe (PaO2/FiO2 ≤100 mmHg). While this definition may facilitate a stratified treatment approach based on severity of hypoxemia, it does not take into account the clinical heterogeneity related to mechanism of injury [8].
Although surfactant alterations are implicated in the pathogenesis of ARDS, surfactant replacement remains of unproven benefit in adult patients. A number of issues relating to human surfactant biology and ARDS may have implications for the design of future surfactant replacement clinical trials and therefore merit closer scrutiny.
Human surfactant system in health
Phospholipid composition of the human surfactant system [9]
Phospholipid subclass
Composition (% of total phospholipid)
Molecular phosphatidylcholine composition of the human surfactant system [11]
PC species
Composition (% of total PC)
Four surfactant proteins have so far been identified (SP-A to SP-D). SP-B and SP-C are hydrophobic proteins, and their primary function is to facilitate the surface tension-reducing characteristics of surfactant phospholipids. SP-A and SP-D are hydrophilic collectin proteins, which are involved in the innate immunity. They have collagen-like domains, which are pattern recognition molecules that facilitate the interaction and removal of a variety of microorganisms and antigens [13].
Surfactant abnormalities in ARDS
Surfactant abnormalities seen in clinical studies of ARDS/ALI patients
Surfactant characteristic
Abnormalities in ALI/ARDS
Surface activity
Reduced surface tension
Phospholipid profile
Reduced levels and fractional concentrations of phosphatidylcholine and phosphatidylglycerol with increase in fractional concentrations of phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and sphingomyelin
Phosphatidylcholine composition
Reduced levels and fractional concentrations of dipalmitoyl phosphatidylcholine with increased fractional concentration of unsaturated species
Surfactant aggregates
Reduced proportion of large aggregates to small aggregates
Surfactant proteins
Decreased alveolar surfactant proteins and increased plasma surfactant proteins
Total phospholipid concentration
Determining total phospholipid concentrations in the alveolar surfactant pool is difficult and depends on many factors including the lavage technique, the surface area lavaged and the amount of lavage fluid recovered. These technical issues are reflected in the variability of the results in published clinical studies. An early study by Hallman and colleagues showed normal surfactant phospholipid concentrations in patients with ARDS [15]. However, subsequent studies have shown consistently lower total BALF surfactant phospholipid concentrations in patients with ARDS [16, 17], particularly in those where the precipitating cause was pneumonia [17].
Phospholipid and phosphatidylcholine composition
The surfactant phospholipid composition in ARDS is characterised by a relative decrease in the fractional concentrations of PC and phosphatidylglycerol with an increase in phosphatidylinositol, phosphatidylethanolamine and phosphatidylserine. The assessment of surfactant composition has been limited by the analytical methods available to quantify PC composition, which have lacked precision in identifying molecular species. Two methodological limitations are particularly important. First, quantifying total disaturated PC as a surrogate for DPPC using osmium tetroxide [15, 21] has an inherent limitation because this technique also measures other disaturated molecular species such as PC16:0/14:0. Second, assessment of the relative content of individual fatty acids by chromatographic techniques does not reveal the specific molecular structure of individual surfactant PC components [20]. When high-performance liquid chromatography (HPLC) was used to analyse specific molecular PC species in a study of BALF from patients with ARDS, lower concentrations of DPPC and increases in other unsaturated PC species - particularly PC16:0/18:1, PC16:0/18:2, PC18:0/18:2 and PC16:0/20:4 - were demonstrated [11].
Surfactant protein concentration
There is an increased total protein concentration in BALF of patients with ARDS [11, 18]. This is coupled with a reduction in surfactant-associated proteins SP-A, SP-B and SP-C [11, 22]. SP-D concentrations in BALF may remain relatively unchanged during the disease process [22].
Surfactant aggregates
Large surfactant aggregates composed of lamellar bodies, tubular myelin and large multilamellar vesicles are highly surface active [23]. During surfactant turnover prior to endocytosis these large aggregates are converted to inactive small aggregates composed of unilamellar vesicles. The exact mechanism leading to this conversion is not fully understood. Reduction in large surfactant aggregates with a relative increase in small aggregates is characteristic of surfactant from patients with ARDS [11, 17]. Reduced levels of large surfactant aggregates are also associated with low survival rates [11].
Possible mechanisms underlying compositional alterations and dysfunctional surfactant in ARDS
Possible reasons for surfactant abnormalities in acute respiratory distress syndrome/acute lung injury
Reduced surfactant synthesis and recycling by injured type II cells
Increased breakdown by hydrolysis and proteolysis
Oxidative injury by reactive oxygen species
Dilution of surfactant material by florid oedema/fluid
Dysfunctional surfactant film formation due to accumulation of plasma constituents
Inhibition by competitive adsorption of plasma proteins
Synthetic dysfunction
In ARDS, synthetic or secretory dysfunction may result from direct or indirect injury to alveolar type II cells. Animal models of hyperoxia-induced direct lung injury show decreased surfactant PC synthesis [24]. In contrast, subcutaneous injection of nitrogenated urethane compound (N-nitroso-N-methyl-urethane), which is toxic to type II cells, leads to increased surfactant saturated PC synthesis and secretion [25]. This paradoxical finding highlights the limitations of animal lung injury models and may be due to the different mechanisms of injury in these studies.
Stable isotope labelling of surfactant precursors is a novel approach to study surfactant kinetics in humans [26]. One in vivo study using such a method suggests there is an increased surfactant PC synthesis in ARDS patients compared with ventilated controls [27]. In contrast to this, sequential quantitative BALF studies in ARDS patients have shown consistently lower concentrations of PC [18] and DPPC [11]. Surfactant SP-D is primarily secreted by type II cells and can be used as a surrogate biomarker for alveolar epithelial injury [28]. Although BALF SP-D levels remain relatively unchanged during the disease course, lower SP-D levels are evident in a subgroup of ARDS patients and are associated with a significant increase in mortality [22]. Variation in the volume of BALF recovery may in part explain these findings. Another possible explanation is variable surfactant synthetic and secretory patterns amongst patients with similar clinical pictures: in other words, phenotypic variation that can only be identified through in vivo characterisation of surfactant metabolism.
Surfactant functional inhibition
During the early stages of ARDS, there is flooding of plasma material (plasma proteins, red blood cells, fibrin and fibrin degradation products) into the alveolar space due to endothelial and epithelial injury. In experimental models, plasma proteins - in particular, albumin, haemoglobin, fibrinogen and fibrin monomers have been shown to impair surfactant function and hence increase surface tension [29]. Reconstitution of protein extracted from BALF supernatant resulted in further deterioration of surface tension, suggesting an inhibitory effect of leaked plasma proteins within the alveolar space [17]. Although the exact mechanisms of surfactant functional inhibition by plasma constituents are not well established, competitive adsorption of plasma proteins [29] and dysfunctional surfactant film formation [30] have both been postulated.
Increased surfactant breakdown by oxidation
Reactive oxygen species are generated as a part of normal oxygen metabolism and are physiologically active in cell signalling. Various reactive oxygen species, including hydrogen peroxide, superoxide and nitric oxide, are released by enzymatic reactions (xanthine oxidase/glucose oxidase/nicotinamide adenine dinucleotide phosphate oxidase) from inflammatory cells. Oxidative disruption of lipids and proteins leads to dysfunctional surfactant and this has been postulated as contributory to the pathogenesis of lung injury [31]. Exogenous surfactant is also subject to reactive oxygen species mediated oxidation, leading to diminished surface tension-reducing characteristics [32].
Increased surfactant breakdown by hydrolysis
Secretory phospholipase A2 (PLA2) activity is increased in BALF from patients with ARDS [33]. PLA2-mediated hydrolysis of surfactant phospholipids contributes directly to surfactant dysfunction and generates free fatty acids that further inhibit surfactant function [34, 35]. Hydrolysis of surfactant PC leads to lysophosphatidylcholine formation, and higher levels of PLA2 activity and lysophosphatidylcholine concentration in ARDS are associated with increased mortality [33, 36].
Surfactant replacement in ARDS/ALI
Fujiwara and colleagues reported the first positive, uncontrolled, clinical study of surfactant replacement in 1980 [37]. In this study, 10 premature neonates with severe respiratory distress syndrome were successfully treated with natural bovine surfactant supplemented with synthetic DPPC and phosphatidylglycerol. Subsequent randomised clinical trials (RCTs) with both natural and synthetic surfactant preparations have shown consistent improvements in lung mechanics, oxygenation and mortality in neonatal respiratory distress syndrome [38].
Several RCTs of surfactant replacement in adults with ARDS have been conducted since 1994 [39–46]. These generally have shown improvements in oxygenation indices but have failed to produce any demonstrable survival benefits [47].
An initial phase I study of synthetic surfactant composed of DPPC without any surfactant proteins (Exosurf) demonstrated its safety profile in 51 patients with sepsis-induced ARDS [39]. In this study, surfactant was nebulised for 5 days continuously and a trend towards mortality benefit was seen in the treatment group. A subsequent larger RCT using the same methods with the same surfactant preparation and study population failed to show any benefits in oxygenation, mortality, length of ICU stay or duration of mechanical ventilation [40]. These negative results may be explained by the lack of surfactant proteins in the surfactant preparation leading to reduced surface spreading characteristics and poor alveolar surfactant deposition by this delivery method (estimated only 5% deposition) [40].
Gregory and colleagues performed a phase II RCT using bovine lung extract containing phospholipids, neutral lipids, fatty acids and surfactant proteins SP-B and SP-C in patients with ARDS. This study enrolled 59 patients and demonstrated improved oxygenation and a trend towards reduced mortality in the surfactant group [41].
A European-based multicentre RCT using a large bolus tracheal instillation of freeze-dried natural porcine surfactant (HL-10) failed to show any mortality benefit. This surfactant preparation consisting of phospholipids (90 to 95%) and SP-B and SP-C (1 to 2%) was instilled for up to three doses (totalling 600 mg/kg). This study of 418 ARDS/ALI patients was terminated early due to an excess of serious adverse events, such as hypotension and hypoxemia, in the treatment group [42].
Spragg and colleagues conducted three RCTs with a surfactant preparation consisting of phospholipids and recombinant SP-C. Following positive results from an animal study [48], a phase II study of recombinant SP-C in 40 ARDS patients showed a good safety profile [43]. This study was followed by a large multicentre phase III RCT of 448 ARDS patients, which showed improved oxygenation but no overall mortality benefit in the treatment group [44]. However, post hoc analysis demonstrated a trend towards mortality benefit for those patients with direct lung injury from aspiration and pneumonia [44]. Following this study, a further phase III RCT was conducted in a large cohort of patients (844 patients) with severe hypoxemia secondary to aspiration and pneumonia. There was no mortality benefit and the study was terminated early due to futility. Furthermore, contrary to the results of previous studies, this study reported a lack of improvement in oxygenation and increased treatment-related serious adverse events [46]. In this study, however, the surfactant preparation process involved a shearing step where it was passed forcefully through a narrow channel to improve suspension and distribution. This shearing step may have resulted in reduced surface tension-lowering properties by possibly exposing the exogenous surfactant to functional inhibition by plasma proteins [46].
Improved gas exchange was noted in nonrandomised clinical studies with bronchoscopic administration of natural porcine surfactant [49] and bovine surfactant [50, 51]. However, these studies were small, noncontrolled and their findings have not been replicated in larger randomised controlled studies.
Possible explanations for the negative results from surfactant replacement studies in ARDS
Characteristics of surfactant replacement RCTs in ARDS/ALI
Number of patients
Surfactant type
Delivery mode and dose
Spragg and colleagues [46]
Multicentre RCT, phase III
Direct lung injury with PaO2/FiO2 ≤170 mmHg (aspiration+ pneumonia)
rSP-C based (synthetic), 1 ml = 1 mg rSP-C and 50 mg PLs
Intratracheal, 1 ml/kg LBW for maximum of eight doses until 96 hours
1. No difference in 28-day mortality, oxygenation or ventilator-free days
1. Differ from other rSP-C studies by no improvement in oxygenation
2. Similar adverse events
2. Shearing step used to improve dispersion may have altered the property
3. Prematurely stopped due to futility
Kesecioglu and colleagues [42]
Multicentre RCT, phase III ALI/ARDS
HL10 - freeze dried natural porcine surfactant (90-95% phospholipids and 1-2% of SP-B and SP-C)
Intratracheal, up to three doses - cumulative doses of 600 mg/kg at 0, 12, 36 hours
1. Increased trend towards mortality in surfactant group with no improvements in secondary outcomes such as oxygenation and SOFA scores
1. Prematurely terminated due to futility
2. More adverse events in the surfactant group
Markart and colleagues [45]
Multicentre RCT, phase I/II
rSP-C based (synthetic), 1 ml = 1 mg rSP-C and 50 mg PLs
Intratracheal, 1 ml/ kg LBW up to four doses in the first 24 hours
1. Improved gas exchange in surfactant group
1. Not designed to assess mortality
2. Normalisation of surfactant PLs and proteins
2. Treatment period was 24 hours
Spragg and colleagues [44]
Multicentre RCT, phase III
221 and 227
rSP-C based (synthetic), 1 ml = 1 mg rSP-C and 50 mg PLs
Intratracheal, 1 ml/kg LBW up to four doses at 4-hour intervals in the first 24 hours
1. No difference in survival or ventilator free days but improved oxygenation in the surfactant group
1. Post hoc analysis for intrinsic ARDS showed trend towards improved mortality.
2. More adverse events in the surfactant group in the first 24 hours after treatment
2. Treatment period was 24 hours
Spragg and colleagues [43]
Multicentre RCT, phase I/II
rSP-C based (synthetic), 1 ml = 1 mg rSP-C and 50 mg PLs
Intratracheal, two groups: group 1, 1 ml/kg LBW; group 2, 0.5 mg/kg LBW, up to four times in the first 24 hours
1. Safety was comparable with no differences in oxygenation and ventilator free days
1. Treatment period was 24 hours
2. Decreased plasma IL-6 in group 1
Gregory and colleagues [41]
Multicentre RCT, phase II/III
Natural bovine lung extract (Survanta; contains phospholipids, neutral lipids, fatty acids, and surfactant proteins with additional DPPC, palmitic acid and tripalmitin)
Intratracheal, three groups: group 1, 8×50 mg/ kg LBW; group 2, 4×100 mg/kg LBW; group 3, 8×100 mg/kg LBW
1. Oxygenation was better with surfactant group 2
1. Small number of patients in each group
2. Trend towards improved mortality in groups 2 and 3
Anzueto and colleagues [40]
Multicentre RCT, phase III
Sepsis-induced ARDS
Exosurf (synthetic), 13.5 mg DPPC/ml
Aerosol, 112 mg DPPC/kg/day for 5 days
1. No difference in 30 day mortality, oxygenation or mean number of ventilation days
1. Only sepsis cohort was studied
2. Aerosolised preparation with poor alveolar deposition
3. No surfactant proteins in the preparation
Weg and colleagues [39]
Multicentre RCT, phase II
Sepsis-induced ARDS
Exosurf (synthetic), 13.5 mg DPPC/ml
Aerosol, two groups: group 1, 21.9 mg DPPC/ kg/day; group 2, 43.5 mg DPPC/kg/ day. Aerosolised for either 12 or 24 hours for 5 days
1. Safety was comparable between three groups
1. Aerosolised preparation with poor alveolar deposition
2. No surfactant proteins in the preparation
Exogenous surfactant composition
Surfactant preparations vary according to their composition, biophysical activity, susceptibility to functional inhibition, preparation technique and associated costs. The relative composition of DPPC and surfactant proteins influences surface tension-lowering characteristics of the exogenous surfactant. Although DPPC is the primary surface tension-lowering molecule, pure DPPC preparations are limited by their lack of surface spreading and adsorption characteristics [39, 40].
Although recent studies with recombinant SP-C-based surfactant preparation showed no mortality benefit [44, 46], manipulation of the composition by adding other surfactant proteins may potentiate its clinical effect. For instance, SP-A has been shown to improve phospholipid adsorption and surface activity and may reduce conversion of large to small aggregates [52, 53]. Developing surfactant preparations that more closely reflect natural human surfactant in the alveolus may therefore improve clinical outcome. In the neonatal population, natural surfactants from lavage or homogenised lung are clinically more effective than synthetic preparations [54]. However, compared to neonates, a large amount of exogenous surfactant is needed to provide adequate treatment in adults. Furthermore, replacement strategies using natural surfactant preparations are costly due to the laborious extraction techniques.
Surfactant delivery methods
Clinical studies with nebulised surfactant preparations conducted in the 1990s were limited by poor alveolar deposition [39, 40]. Much of the published work since then has evaluated surfactant delivery via intratracheal instillation [41–46]. A large quantity of surfactant material is generally delivered by this route, which may be of benefit in counteracting the effect of surfactant inhibition [42]. However, this large quantity delivery can result in flooding of the central airways and lead to increased airway resistance and worsening of hypoxemia. In animal models, intratracheal administration leads to poor surfactant deposition in the collapsed alveoli [55]. An alternative is sequential bronchoscopic administration, which has been evaluated in a number of uncontrolled studies. Bronchoscopic sequential segmental administration of natural bovine surfactant was associated with improved PaO2/FiO2 ratios coupled with improved ventilation-perfusion matching in the lungs [50], as well as relative normalisation of surfactant composition and function [51]. However, this technique is time consuming and resource intensive and may not be feasible in clinical practice or large RCTs.
Uniform delivery of surfactant material to both affected and unaffected parts of the lung might improve atelectasis in affected areas, but may be detrimental in unaffected areas. Computerised tomography has demonstrated the heterogeneous distribution of lung injury in ARDS, with the lower zones of the lungs tending to be most affected [56]. Computerised tomography images may help to guide targeted bronchoscopic administration of exogenous surfactant to affected lobes.
Clinical heterogeneity of surfactant biology in ARDS
ARDS encompasses a variety of aetiologies leading to an apparently common diffuse alveolar damage. Consequently, surfactant alterations are attributed to several pathological mechanisms, which have not been fully explored by human studies. Specifically, patterns of surfactant synthesis and metabolism have not been characterised in ARDS. Current ARDS diagnostic definitions are uninformative with regards to the degree of alveolar injury, the dynamic surfactant pool and surfactant metabolism. Phenotypic characterisation of groups with surfactant synthetic dysfunction may help to target those patients most likely to benefit from exogenous surfactant replacement. For example, reduced surfactant synthesis in neonatal respiratory distress syndrome provides the best human surfactant-deficient lung injury model - and in this context, exogenous surfactant replacement leads to reduced morbidity and mortality [38].
Where there is intact alveolar synthetic function, assessment of the degree of surfactant inhibition or breakdown by hydrolysis and oxidation may be of value. Testing of patient's endogenous surfactant against the exogenous surfactant material may provide important clues to the degree of functional inhibition that may be encountered during supplementation. Attempts to counteract this by instilling large amounts of exogenous surfactant may result in an increased risk of serious adverse events [42]. Addition of other surfactant proteins such as SP-A or SP-B may counteract functional inhibition by plasma constituents and has been shown to improve the efficacy of exogenous surfactant preparations in in vitro studies [57, 58].
The combination of increased PLA2 activity in BALF and increased concentrations of lysophospholipids may serve as markers of phospholipase-mediated surfactant phospholipid breakdown. This breakdown could be counteracted by PLA2-resistant surfactant analogues such as phospholipase-resistant diether lipids [59], PLA2 inhibitors or SP-A [60].
Exogenous surfactant subjected to oxidation has reduced surface activity [61, 62] and this may have contributed to the negative clinical outcomes in ARDS trials. Oxidative metabolites of phospholipids can be quantified by mass spectrometry [63]. These oxidised phospholipids may be used as a surrogate to assess the degree of oxidation mediated surfactant breakdown. The potential of oxidised phospholipids as biomarkers in this context has not been fully explored. SP-A and SP-D have antioxidant activity [64] and augmentation of these proteins or other endogenous antioxidants such as superoxide dismutase, vitamin E, melatonin and ebselen may moderate oxidative breakdown of exogenous surfactant in those with high levels of surfactant oxidation [65].
Can we phenotype patients according to surfactant synthetic function?
Clinical trials of exogenous surfactant have not so far phenotyped patients according to alveolar surfactant synthesis, metabolism and degree of functional inhibition prior to replacement strategies. Improved characterisation of synthetic ability and surfactant function may identify selected patient groups that may benefit from specific surfactant therapies individualised according to the underlying pathophysiological processes.
Knowledge of surfactant biology has evolved over the last 50 years, providing valuable insight into alveolar surfactant physiology in lung injury. However, there remain substantial knowledge gaps that need to be addressed by future research. An ideal surfactant material that mimics the properties of human surfactant is lacking and research should focus on refining surfactant preparations that incorporate all surfactant proteins as well as developing measures to reduce the impact of functional inhibition. Targeting of surfactant delivery to the lobes that are most affected may also be of benefit. Finally, and most crucially, the target population needs to be characterised according to surfactant synthetic function using the best available technology, including nonradioisotope labelling of surfactant precursors. This characterisation may permit stratification of the ALI/ARDS population according to the surfactant synthetic capability of alveolar type II cells and provide a rational basis for targeting exogenous surfactant interventions.
acute lung injury
acute respiratory distress syndrome
bronchoalveolar lavage fluid
dipalmitoyl phosphatidylcholine
- FiO2:
proportion of oxygen in the inhaled air
high-performance liquid chromatography
- PaO2:
partial pressure of arterial oxygen
phospholipase A2
randomised controlled trial
surfactant protein.
All authors are funded in part by the University Hospitals Southampton NHS Foundation Trust - University of Southampton Respiratory Biomedical Research Unit which received a portion of its funding from the United Kingdom Department of Health's National Institute of Health Research Biomedical Research Unit funding scheme.
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- Nakos G, Kitsiouli E, Hatzidaki E, Koulouras V, Touqui L, Lekka ME: Phospholipases A 2 and platelet-activating-factor acetylhydrolase in patients with acute respiratory distress syndrome. Crit Care Med 2005, 33: 772-779. 10.1097/01.CCM.0000158519.80090.74View ArticlePubMedGoogle Scholar
- Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T: Artificial surfactant therapy in hyaline-membrane disease. Lancet 1980, 1: 55-59.View ArticlePubMedGoogle Scholar
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- Anzueto A, Baughman RP, Guntupalli KK, Weg JG, Wiedemann HP, Raventos AA, Lemaire F, Long W, Zaccardelli DS, Pattishall EN: Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med 1996, 334: 1417-1421. 10.1056/NEJM199605303342201View ArticlePubMedGoogle Scholar
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- Kesecioglu J, Beale R, Stewart TE, Findlay GP, Rouby JJ, Holzapfel L, Bruins P, Steenken EJ, Jeppesen OK, Lachmann B: Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2009, 180: 989-994. 10.1164/rccm.200812-1955OCView ArticlePubMedGoogle Scholar
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- Spragg RG, Lewis JF, Walmrath HD, Johannigman J, Bellingan G, Laterre PF, Witte MC, Richards GA, Rippin G, Rathgeb F, Häfner D, Taut FJ, Seeger W: Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004, 351: 884-892. 10.1056/NEJMoa033181View ArticlePubMedGoogle Scholar
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text:
At first when I found the flag flying south,
southeast, flexing and snapping, I knew that
the hawk would be like sharp spikes on strained silk.
Now I am drifting back to North Dakota,
drifting back to horizons full of white,
back to cornfields boarded up by blizzards.
Trees and power lines pulled to earth by ice,
narrow roads with zones of snow antenna
high. I have come to walk in those uncommon
days; I have come to feel the farmhouse souls
assuage me in a parka lined with fur.
The hawk would pound and pound upon the door
for hours at a time; we could not help
but hear. I placed my hand against the door,
recoiled from the cold. He pounded still.
I waded through the thaw of warmer days
and watched the river rising to the levee;
heard the hawk's faint whisper turning into stone.
Now I can hear the flag flexing and snapping,
though today, still, I feel my fingers burn.
© Copyright 2017 teargen. All rights reserved.
Status: Finished
Genre: Memoir
Poem / Humor
Poem / Non-Fiction
Poem / Non-Fiction
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subset: commoncrawl


text:
i hate everyone
they're so immature
running around with all their petty problems
and their eyes full of money
money, money
its all that matters these days
i hate everyone
they're so immature
brains full of material
and a heart full of greed
i hate eveyone
they're so immature
© Copyright 2017 sweet agony xo. All rights reserved.
Status: Finished
Genre: Poetry
Haha, I love this poem. It's so true.
Boys worrying about whether or not they get on a team or if they're the strongest.
Girls worrying about their looks and popularity.
Though, almost every immature person worries so much about their freaking money. They should be glad they have any with their greedy personalities.
Anyways... Like I said, I love this poem. ^_^
Nice poem. Fuck those immature morons.
They have no fucking idea about how REAL problems work.
Sadly many do worry about material things and vanity...A good poem...Well written
This is literally how I feel all the time. It's very relatable. In High School these were my exact thoughts! These poems are amazing! Keep it up!
And don't feel obligated to read my book until you have the time or if you simply don't like it. I'll completely understand! :)
Book / Young Adult
Short Story / Humor
Short Story / Other
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text:
90% of business leaders confident of prospects
British business leaders are more confident than at any time during the recession that they will make it through the downturn, research reveals, adding to the growing optimism about the economy.
A survey from Clydesdale Bank shows that 90% of business managers now say they are confident they will make it through the recession, with a third saying they are certain they will not go under.
The research also suggests the downturn may not have had as savage an effect on some companies' business as previously thought. Clydesdale said only a third of the companies it spoke to had actually suffered a reduction in business during the downturn so far.
While economists believe the UK economy began growing again over the summer — and that the third quarter GDP figures due to be published towards the end of next month will provide official confirmation of this — there is still scope for further problems. Unemployment figures due this week are expected to show another sizeable leap in joblessness to more than 2.5 million, with most projections suggesting the numbers out of work are unlikely to begin falling before the middle of next year.
Mike Williams, a Clydesdale Bank executive, said its research suggested business leaders were becoming increasingly confident about their prospects. "These figures are promising and show that businesses are beginning to regain confidence," he added.
"This is a positive sign: where confidence exists growth often follows."
Belfast Telegraph


text:
July 17, 2013 | 4:49PM
"Varsity Blues" Is Not Your Typical Texas High School Football Film - It is Much Better
In Texas, soccer teams do not enjoy video games, they interact in severe, civilized warfare. Since substantial killing and scorched Earth techniques are not acknowledged in present day modern society, Texas fans and their teams find the next ideal end result-win Each bloody sport, hopefully with whole domination so there is no need to have for bragging legal rights.
This would be real for the West Canaan Coyotes, whose coach Bud Kilmer (Jon Voight) is in search of his 23rd division title in 35 several years of coaching. Kilmer has been around long adequate to coach his previous players' sons, and then some. He is so driven, targeted, horrible and identified enough to acquire that he will sacrifice the extremely well being of his possess gamers to get the occupation carried out.
Jon Voight is perfect in this function. Kilmer is self-centered, self-absorbed and incredibly needy for electrical power, adulation and turf good results. Football is close to religion in Kilmer's globe, and he is god. 1 of Kilmer's mottos is "Never ever demonstrate weakness, the only ache that issues is the soreness you inflict."
When his star quarterback, Lance Harbor (Paul Walker), is injured simply because he was taking part in when he should not have even been on the discipline, his substitution, John Moxon (James Van Der Beek) have to phase into the leadership role.
Even even though he is a Texas high school soccer player with some talent, Moxon is every thing he need to not be-soccer is not his priority, he needs to go to higher education to get an training fairly than perform soccer, and he gets caught reading through a novel hidden in the perform book he is intended to be studying. Each ought to have credit history for lifting Varsity Blues up to a greater degree over and above sheer, cine mindless enjoyment.
This is the ideal guide I have study in a long while, the tale is basic
enough but the several themes that run by means of it makes it so a lot a lot more. I have
only scratched the floor of this ebook, it leaves you thinking about it for a
extended time following it's concluded. I see it as a ebook that requirements to be study more
than as soon as as I feel you will obtain a lot more with each studying.
Lately, YouTube announced they are permitting advertisers in Australia to get look for keywords for their video clips. I never ever understood YouTube had the choice of Spend-Per-Click on adverts for films posted there. With these YouTube spend-per-click advertisements for video clips, it is starting to blur the lines among what is advertisement and what is enjoyment.
July 17, 2013 | 4:47PM
SS501 Kim Hyun Joong - What's Behind the 4D Personality?
This is the best book I have go through in a prolonged whilst, the story is basic
enough but the numerous themes that operate via it can make it so a lot a lot more.
The story is about two boys divided by lifestyle, faith, modern society, a war and
a real daily life fence. They are brought jointly by their common require for a
friend and this is some thing that can come about due to their innocence. They
understand that what's happening to them is not correct but are unaware of the
real horrors guiding the issues that are taking place all around them. This
innocence allows their friendship to develop without having the understanding that they
are really on diverse sides and with no them realising that indirectly
they are the other folks reason for currently being the place they are.
Both boys have been torn away from the daily life they liked, from family and
close friends. In their own way they are equally prisoners, Shmuel in the accurate perception
of the phrase, trapped in a concentration camp without foodstuff, adore or hope.
Bruno, although he life in a house with meals and servants is still trapped
in a world with no close friends and the comforts he is utilized to. Assembly at the
fence is escape for the two boys, it brings a tiny normality to their lives.
Bruno's loved ones does not adapt to their move, Mother gets far more and far more
depressed, Gretal, his sister, although only thirteen appears to a significantly more mature
soldier for some focus, equally because of the social isolation.
The only part of the e-book I identified a tiny difficult to recognize was the
segment in which Shmuel was in the kitchen of Bruno's house. I considered at 1st
it was due to the fact the soldier understood that they had been meeting and it was to
punish them each. But this did not materialize as the purpose. It did lead to
Bruno's denial of their friendship and the beating of Shmuel but I consider the
story would not have endured if this part experienced been left out, it seemed as well
much of a coincidence that of all the boys in the camp he was picked for the
job in the kitchen area.
I predicted the ending nicely before it transpired, but this did not mute the
impact of it, the horror of what was happening and the despair of understanding
the inevitability of their steps. The only conserving grace for me once more was
their innocence, they were unaware of the real horror of what was about to
occur to them, they couldn't graphic anything so awful so they ended up spared
from the terror that these around them felt in those previous couple of seconds.
Archived Diary Posts


text:
Reviews (1)Add review
GFs Vday Gift 02-19-2017
I've never bought clothes as a surprise gift so I was hesitant to start with a dress. I wasn't 100% on her size but with it being a shirt dress I took a chance on M and was satisfied with the look. I wish I could post a photo. She looks great, the shipping was lightning fast, and most of all I love supporting a brand that supports lesser known board riders. #truetothis


text:
This list contains items like Kristin Kreuk and Ron Perlman
If you are wondering, "Who are the actors from Beauty and the Beast?" or "Who starred on Beauty and the Beast?" then this list will help you answer those questions.
In most cases you can click on the names of these popular Beauty and the Beast actors and actresses to find out more information about them. If you're looking for a particular Beauty and the Beast actor or actress, then type their name into the "search" bar to find them directly.
- 1
Alwyn Kurts Homicide, Cop Shop, Rush
- 2
Armin Shimerman Star Trek: Deep Space Nine, Beauty and the Beast, Evil Con Carne
- 3
Brian J. White Beauty & the Beast, The Shield, Moonlight
- 4
Bridget Regan Beauty & the Beast, Legend of the Seeker
- 5
Chris Mulkey Twin Peaks, Beauty and the Beast, Bakersfield P.D.
- 6
David Greenlee Beauty and the Beast, Fame
- 7
Derryn Hinch Dancing with the Stars, Beauty and the Beast
- 8;
- 9
Edward Albert Beauty and the Beast, Power Rangers, Falcon Crest
- 10
Ellen Geer Beauty and the Beast, The Jimmy Stewart Show
- 11
Jay Bunyan Beauty & the Beast, Neighbours, Top of the Lake
- 12
John Forgeham Footballers' Wives, Prime Suspect, Celebrity Fit Club
- 13
Jo Anderson Beauty and the Beast, Sisters, From the Earth to the Moon
- 14
Kristin Kreuk Smallville, Beauty & the Beast, Law & Order: LA
- 15
Lewis Smith Beauty and the Beast, North and South, The Man Who Fell to Earth
- 16
Linda Hamilton Chuck, Beauty and the Beast, Hercules
- 17
Rachel Skarsten Beauty & the Beast, Lost Girl, Birds of Prey
- 18
Ren Woods Beauty and the Beast, We've Got Each Other
- 19
Rob Stewart Beauty & the Beast, Nikita, Painkiller Jane
- 20
Roy Dotrice Beauty and the Beast, Shaka Zulu, Mr. & Mrs. Smith
- 21
Sendhil Ramamurthy Heroes, Beauty & the Beast, Covert Affairs
- 22
Stephen McHattie Beauty and the Beast, Look What's Happened to Rosemary's Baby, XIII: The ...
- 23
Stuart Wagstaff Beauty and the Beast
- 24
Ron Frazer The Mavis Bramston Show, Birds in the Bush, Father^! Dear Father In ...
- 25
Jay Acovone Beauty and the Beast, Search for Tomorrow, Hollywood Beat
- 26
Ritch Brinkley Beauty and the Beast, Dolly
- 27
Nicole Gale Anderson Beauty & the Beast, Ravenswood, Jonas L.A.
- 28
Austin Basis Beauty & the Beast, Life Unexpected
- 29
Max Brown Beauty & the Beast, The Tudors, Spooks
- 30
Ron Perlman Sons of Anarchy, Adventure Time, Teen Titans
- 31
Noel Ferrier Beauty and the Beast
- 32
John Laws Beauty and the Beast
- 33
Shantel VanSanten Beauty & the Beast, One Tree Hill, Gang Related
- 34
Rex Mossop Beauty and the Beast
- 35
Nina Lisandrello Beauty & the Beast
- 36
Clive Robertson Beauty and the Beast


text:
French Lamb Salad
|Cold roast lamb
|1 Pound (Preferably Medium Rare)
|Olive oil
|1⁄4 Cup (4 tbs)
|White wine vinegar
|2 Tablespoon
|Chopped mint/1 tablespoon dried leaf mint
|2 Tablespoon
|To Taste
|Freshly ground pepper
|To Taste
|Green onions
|4 , chopped
|Cooked green peas
|1 Cup (16 tbs)
|Head of lettuce
|Mint sprig
1. Prepare the lamb by cutting into 3/4-inch cubes.
2. To make dressing, into a bowl large with oil enough to hold lamb and vegetables whisk in vinegar, mint, salt and pepper.
3. Stir in lamb cubes and green onions to coat with dressing and gently stir in peas.
4. Serve immediately or cover and refrigerate up to 24 hours.
5. Immediately before serving, shred lettuce and stir into lamb salad.
6. Into a serving dish spoon the mixture and garnish with mint sprigs.
Recipe Summary
Rate It
Nutrition Rank
Nutrition Facts
Serving size
Calories 396 Calories from Fat 258
% Daily Value*
Total Fat 29 g44.5%
Saturated Fat 8.9 g44.7%
Trans Fat 0 g
Cholesterol 75 mg25%
Sodium 177.7 mg7.4%
Total Carbohydrates 11 g3.5%
Dietary Fiber 4.8 g19.3%
Sugars 3.5 g
Protein 25 g49.1%
Vitamin A 146.3% Vitamin C 51.3%
Calcium 6.3% Iron 11.8%
*Based on a 2000 Calorie diet


text:
Patricia Carroll analyses and celebrates living things and the essence of creation through her abstract-expressionist paintings. She perceives mystery everywhere and attempts to depict this using textures, mark-making, overlays and washes of a limited palette of mainly transparent acrylics. The eye dances throughout, alighting here and there in sheer pleasure.
"As I paint, my personal and cultural experiences affect how I proceed. I lose myself in movement, feelings, thoughts - all merging. I am immersed and alive."


text:
Top Linksmain detailsbiographyby votesphoto galleryquotes
Filmographiesby yearby typeby ratingsby votesby TV seriesby genreby keyword
Did You Know?photo galleryquotes
Sid Garner (Character)
from The Hangover (2009)
|Photos (See all 5 | slideshow)
|Related Videos (see all 15)
Alternate Names:
FilmographyEdit Credits
- The Hangover Part III (2013) Played by Jeffrey Tambor (as Sid)
- The Hangover Part II (2011) Played by Jeffrey Tambor
- The Hangover (2009) Played by Jeffrey Tambor (as Sid)
... aka "Stopping in Vegas on the Way to a Wedding" - Israel (English title)
Additional Details
Plot Keywords:
Fun Stuff
[last words]
Sid: [end-of-tether] Your mother and I can't take this any more!
[has a heart attack]
See more »
You may correct errors and omissions on this page directly. Clicking the 'Update' button will take you through a step-by-step process.


text:
A character concept from a book I worked on. Check out the full versions at http://slugnyc.tumblr.com/
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text:
First settled in 1882, and incorporated as a town in 1898, Wolseley's history has been kept alive in the community throughout the years. Come take a walk on our Swinging Bridge!
Hanley is a diverse community located 56 kilometers south of Saskatoon on a four lane divided highway.
At our Shellbrook Campground you can register at our Tourist Booth. Once registered there is a pool available right in our campground! Don't forget about our playground program - your kids can play while you get a golf game in ;)
The Village of Rama is a quaint community situated within one hour of hunting, fishing, swimming, snowmobiling, skiing, shopping, and many other amenities. We have a small hotel and a huge amount of hospitality.
Town of Maidstone
Tourism Center East Saskatchewan


text:
With Instructables you can share what you make with the world, and tap into an ever-growing community of creative experts.
These are necessary ingredients to make good Bibim Myun.
This is Korean traditional vegetable, called Kimchi. It is made with a variety of seasonings.
After David and I put Kimchi into a bowl, we poured a little bit of sesame oil on it.
We also put some of seasoning squid on it.
This is the main spicy sauce that comes out with the noodles.
The ingredients all together with the sauce on it.
Lastly, we added some sugar on it.
At the same time, we were cooking noodles by boiling water.
Boiled noodles.
We cooled it down by using cold water.
Lastly, we put some seaweed on the noodles.
Done! Enjoy!
How To Make Instant Pastaby trevor234
Nerikomi Pastaby Joerg Engels
Homemade Semolina Pastaby How2MakeThat
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text:
|The Competitive Intelligence
Learn MoreSchedule A Live Demo
Download Cipher's Guide to Selecting CI Software
|The Competitive Intelligence
Learn MoreSchedule A Live Demo
Download Cipher's Guide to Selecting CI Software
Build and share customized dashboard views to see what's most important to you, populated with the most up-to-date data and information. Subscribe to and monitor companies at the click of a button, seeing what matters most on one page. Take it a step further and toggle between your competitor overviews in one click.
View, edit, create and share dynamic analysis all in one portal. Use the Knowledge360® chart builder to determine and create the best visualization for your data and information, adjusting the chart type in one click. Spend less time creating the visualizations and more time conducting analysis on customers and competitors in this interactive module.
Use the built-in advanced report and newsletter builder to automate and simplify more of the formatting, production, and distribution process that goes into sharing CI, getting key insights to your team more efficiently and effectively. Use one of the pre-defined templates or create your own to streamline your report-building process.
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Enterococcus faecalis is a major cause of hospital-acquired infections and also plays a key role in the dissemination of antibiotic resistance and virulence genes to other bacterial pathogens. This application seeks continued support for basic studies of a unique peptide-based signaling system that allows cells carrying an antibiotic resistance/virulence plasmid called pCF10 to regulate expression of genes involved in resistance transfer and virulence. The key players in the signaling system include the cCF10 peptide pheromone (signal molecule) and the iCF10 peptide pheromone inhibitor which antagonizes cCF10. The receptor for these peptides is a transcription factor called PrgX, which regulates expression of the pCF10 prgQ operon encoding the virulence and plasmid transfer genes. The pheromone response machinery comprises a sensitive and robust biological switch, where multiple regulatory circuits act in concert to amplify the direct response to pheromone, and to enable the host cell to sense different kinds of environmental cues. Post-transcriptional regulatory mechanisms involving novel small RNAs also play a major role in the pheromone response. The proposed studies are focused on elucidating the quantitative effects mechanistic aspects of various regulatory circuits, and on determining the mechanisms by which the pheromone-induced state can be returned to basal levels of expression following transfer of the plasmid to a new host. This work will reveal insights into regulation of microbial virulence by cell-cell signaling, applicable to many organisms, and may also facilitate new strategies for development of antimicrobial agents.
This research investigates the process by which bacteria communicate with one another using small molecule signals. In this case the signal causes cells carrying antibiotic resistance genes to transfer copies of these genes to other cells. The bacterial species involved is Enterococcus faecalis and the transfer process increases the virulence and antibiotic resistance of strains that cause infections in hospitals. The basic knowledge gained from this research may provide new insights into the development of more effective forms of antimicrobial chemotherapy.
|Bhatty, Minny; Cruz, Melissa R; Frank, Kristi L et al. (2015) Enterococcus faecalis?pCF10-encoded surface proteins PrgA, PrgB (aggregation substance) and PrgC contribute to plasmid transfer, biofilm formation and virulence. Mol Microbiol 95:660-77
|Johnson, Christopher M; Chen, Yuqing; Lee, Heejin et al. (2014) Identification of a conserved branched RNA structure that functions as a factor-independent terminator. Proc Natl Acad Sci U S A 111:3573-8
|Cook, Laura C C; Dunny, Gary M (2014) The influence of biofilms in the biology of plasmids. Microbiol Spectr 2:0012
|Chatterjee, Anushree; Cook, Laura C C; Shu, Che-Chi et al. (2013) Antagonistic self-sensing and mate-sensing signaling controls antibiotic-resistance transfer. Proc Natl Acad Sci U S A 110:7086-90
|Caserta, Enrico; Haemig, Heather A H; Manias, Dawn A et al. (2012) In vivo and in vitro analyses of regulation of the pheromone-responsive prgQ promoter by the PrgX pheromone receptor protein. J Bacteriol 194:3386-94
|Johnson, Christopher M; Haemig, Heather H A; Chatterjee, Anushree et al. (2011) RNA-mediated reciprocal regulation between two bacterial operons is RNase III dependent. MBio 2:
|Cook, Laura; Chatterjee, Anushree; Barnes, Aaron et al. (2011) Biofilm growth alters regulation of conjugation by a bacterial pheromone. Mol Microbiol 81:1499-510
|Dunny, Gary M; Johnson, Christopher M (2011) Regulatory circuits controlling enterococcal conjugation: lessons for functional genomics. Curr Opin Microbiol 14:174-80
|Chatterjee, Anushree; Johnson, Christopher M; Shu, Che-Chi et al. (2011) Convergent transcription confers a bistable switch in Enterococcus faecalis conjugation. Proc Natl Acad Sci U S A 108:9721-6
|Johnson, Christopher M; Manias, Dawn A; Haemig, Heather A H et al. (2010) Direct evidence for control of the pheromone-inducible prgQ operon of Enterococcus faecalis plasmid pCF10 by a countertranscript-driven attenuation mechanism. J Bacteriol 192:1634-42
Showing the most recent 10 out of 30 publications


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DF: Okayyyy...maybe I'll be cruising on over to your website and taking
a look see to find myself a hib as a houseplant...yep, that would pretty
much cheer me up out of the end of the winter blues...Thanks for the
info., your Honor. :-)
Hills, IA
"The most beautiful thing we can experience is the mysterious."
--Albert Einstein
--- On Wed 02/09, David Franzman < firstname.lastname@example.com > wrote:
From: David Franzman [mailto: firstname.lastname@example.com]
To: firstname.lastname@example.com
Date: Wed, 9 Feb 2005 10:01:32 -0800
Subject: Re: [CHAT] Update on A Touch
Hi Melody

Well I guess DF will do!

Hibs are actually
completely edible. They make tea with the flowers and in
Mexico they
make a drink from the leaves. So no worries with pets and or
kids.
As far as houseplants they do just fine. On one of the Hibiscus

groups we just heard from a women in Ontario Canada who has had
her's for 20
years. It's outside in the summer and inside next to a
window in winter.
She said she gets occassional flowers even in
winter. I think Auralie said
she's had a Hib for over 20 years as
well didn't you Aurailie?

Ok, this group is humbling and I'm back
to plain ol' DF. It is amazing how
much like family this group is.
You can leave for awhile but you are always
welcome when you come
Original Message -----
From: "Melody " <email@example.com>
To:
<firstname.lastname@example.com>
Sent: Wednesday, February 09, 2005 2:38
AM
Subject: RE: [CHAT] Update on A Touch

> Dear Your
Honorific Representative of the Bootless Wonders:
>
> Please be
advised that your title is too long to fit our computer screens
> so
we've decided to shorten it to "DF".
>
> Hope you have a wonderful
selling season. Everytime I visit your website
> I am so tempted to
buy, buy, buy...at least one of everything! I'm sure
> there are
plants out there that are easier to grow, but boy! almost
> nothing
can compete with their magnificent glory! How do they do as
>
houseplants? With cats and small dogs? And children? Toxic at all?
Do
> they require high light levels? Please advise.
TIA!
>
>
>
> Melody
> Hills, IA
>
> "The most
beautiful thing we can experience is the mysterious."
> --Albert
Einstein
>
> --- On Tue 02/08, David Franzman <
firstname.lastname@example.com > wrote:
> From: David Franzman [mailto:
email@example.com]
> To: email@example.com
> Date: Tue, 8 Feb
2005 17:07:07 -0800
> Subject: [CHAT] Update on A Touch
><br
Join Excite! - http://www.excite.com
The most personalized portal on the Web!
To sign-off this list, send email to firstname.lastname@example.com with the
message text UNSUBSCRIBE GARDENCHAT


text:
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text:
More Videos...
Honda CBR 1000RR runs 6.98 et in the 1/4 mile! No wheelie bar drag bike
http://www.dragbikelive.com - The Dragbike Live.com film crew was on location during the Manufacturers Cup Finals held November 11-13 2011 at SGMP in Valdosta Ga. filming the event and captured the exclusive video of Frankie Stotz, rider for Stotz Racing aboard his turbocharged Honda CBR 1000RR street bike became the first turbo charged streetbike to break into the six second zone!
bmw 1000 rr vs cbr 600 picada 2


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This star rating is the opinion of the property owner only. A Self-Rated hotel has not been assessed by the AA or Visit Britain, whose official star ratings we use across LateRooms.com.
Turim Europa Hotel4 Self rated
R. São Sebastião da Pedreira, 19, Lisboa, 1050-206
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About the hotel
The Turim Europa Hotel, located in the city center, between the Marquês de Pombal and Saldanha, is recognize by high standards of quality, refinement and good taste. Modern hotel of charm in Lisbon, the Turin Europe offers unique moments, where the description and personalization are a constant. Guests may also enjoy a comfortable lounge, situated in front of the reception, free wi-fi Internet access, a well-lit living room television, 4 well-equipped meeting rooms as well as room service, laundry and private garage (depending on availability).
Read MoreLess
Unfortunately this hotel is currently not open to bookings through LateRooms.com
Facilities Show/hide
- Main
- Hotel Non-Smoking Throughout, Disabled Facilities, Air conditioning in rooms, 24 Hour Reception, Cots available, Safety Deposit Box, Tea/Coffee making facilities in each room, Hairdryer in each room, Minibar in each room, Telephone In Each Room, Limited Hours Room Service, Limited room service for hot food, Laundry/Valet Service, Wake Up Call Available, Currency Exchange, Doctor on call, Ground floor bedrooms, Lift to all floors
- Parking
- Car parking available onsite
- Business
- Wi-Fi Available, Meeting Facilities, Wi-Fi Available In Public Areas, Wi-Fi Available In Rooms, Business Centre, Translation Service
- In Room Entertainment
- TV, Satellite TV, Radio
- Accessibility
- Disabled Access Public Areas, Disabled Access Bedrooms, Disabled toilets on ground floor, Wheelchair Access, Wheelchair Access To Reception, Wheelchair Access To Bar, Wheelchair Access To Conference Rooms
- Dining
- Lounge Menu, Bar, Breakfast to go
- Leisure
- [Channels] News, [Channels] Foreign (European), [Channels] Music, [Channels] Childrens
Useful Info Show/hide
- 14:00 00:00
- 12:00
- Up to 12 years old
- The price shown is based on the occupancy and dates you have searched for. Prices and availability are subject to change based on the arrival date, number of nights and occupancy searched for. All prices are inclusive of all local taxes.
- Pets are not allowed
Customer Reviews
Our reviews are from genuine LateRooms.com customers. We verify that the customer has stayed before leaving a review.
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Doggy Day Care in Crab Orchard, KY
Drop off your dog at your sitter's home in the morning, and pick them up in the evening.
Fun, Playful, Energetic Dog Sitter
Berea, KY, 40403
Dog Boarding, House Sitting, Drop-In Visits, Dog Walking
About: Hi there! My name is Bailey. I am a 24 year old graduate from Berea College with my degree in Cellular and molecular biology. I currently work in L... (more)
Animal lover
Berea, KY, 40403
Drop-In Visits, Doggy Day Care, Dog Walking
About: I very much enjoy being around and playing with dogs. I have had several pets throughout my life (4 Pomeranians, 1 Australian Sheppard mix, 2 Cocke... (more)
Life is better with paws
Richmond, KY, 40475
House Sitting, Drop-In Visits, Dog Walking
About: I love dogs and tend to find a dog everywhere I go, sometimes I prefer them over people (LOL). I have raised and provided for my 3 year old German ... (more)
Experience exceptional service and a personalized match
From start to finish, we'll handle all the details for you.Learn About Premier
Rover also offers doggy day care in:
|Brodhead, KY
|Cartersville, KY
|Conway, KY
|Hyattsville, KY
|Lancaster, KY
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|Willailla, KY
We've been there, cancelling meetings or plans with friends to make sure you can be there for your dog. Good news: You can easily find and book doggy day care in Crab Orchard on Rover. Whether you need a one-time daytime pet sitter or someone to take care of your beloved pet every weekday, we've got you covered. Care for your dog and peace of mind for you are just a few clicks away. If you already have a favorite overnight sitter, ask them if they offer day care too. Or, if you've never used Rover, this is the perfect opportunity to find a new best friend for your dog when you're at work. We can help you find a sitter who'd love to watch your dog.


text:
Bat Devil Child Costume LItem #: 16295 L
Bat Devil Child Costume L
The Bat Devil Child Costume L is the child fit pendant of the adult Bat Devil Costume M / L. The devilish child costume consists of a spaghetti strap top with buckles, a tulle mini skirt, laced arm warmers, cobweb design bat wings and a hairband with devil horns. To look absolutely authentic in your Halloween costume you should get the Trident devil fork. Leggings and shoes are not included.
Size: L is German child size 152 to 170
Material: 100% Polyester


text:
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- Quality: High
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This Gif entitled League tits was created from the youtube video 3 years ago. It uses 18 frames per second and is displayed at 640px resolution. This animated image plays for 6 seconds, was built with high quality and an estimated weight of 14.72 MB for download. This animation was originally created from the video from 01:17 to 01:23.
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Are you looking for Personalized Gifts in Suffolk NY? Hotfrog showcases 18 popular businesses related to Personalized Gifts near Suffolk NY! Find a specific suburb using the left navigation.
Manorville, NY
Personalized Christmas Ornaments, Hand painted and personalized gifts for babies and children. Piggy banks, dog puppy ornaments, rocking chairs, wall plaques, Piggy Banks, Dog Breed Ornaments and Picture Frames
Personalized Christmas GiftsPersonalized Christmas OrnamentsPiggy BanksParty Favors
Commack, NY
Personalized Gifts from Your Favorite Photos...Because People Like to be Remembered!...Visit our charming online boutique featuring glossy tiles, glass cutting boards
Personalized KeepsakesAnniversary GiftsGlass Cutting BoardsPhoto Keepsakes
Middle Island, NY
Uniquely Creative Gifts is a personal gift shopping service.I'll do all the work, and you get all the credit. Welcome to my world of creativity and imagination. My name is Tina Santillo and I would love to be your person…
Gifts For Men
Deer Park, NY
Chocolate Candids creates delicious, personalized chocolate favors, lollipops,cookies, cake toppers, corporate and gift baskets utilizing your favorite photo, personal message or graphics and print the image directly on …
Promotional GiftsSweet Sixteen FavorsTeacher GiftsBridal Party Gifts
Tresstina Baby and Children's Boutique is a luxury boutique featuring stylish and functional baby gear, room decor, and unique gifts for babies, young children and their parents. Tresstina offers a carfeully selected se…
Gifts For BabiesBaby Gifts
Central Islip, NY
Star Promoz provides support and promotional products to businesses across the United States, and locally hosts the most efficient and effective business networking event on Long Island – The Lunch Break Star P…
Personalized PencilsGolf Balls MugsWholesale T ShirtsEmployee Awards
East Northport, NY
MattLain Printing and Promotions on Long Island offers the best printing solutions, access to the best printing house for your job, and personal supervision of your projects. We also can help you choose the most cost-eff…
Huntington, NY
For the past 6 years Interthread Embroidery has been partnering with businesses like yours, supplying unique and effective promotional products with lasting value
Effective Promotional ProductsCorporate ApparelT Shirts
huntington, ny
Baby GiftsCorporate Apparel
east islip, ny
Our custom party favors - personalized candy bar wrappers & gifts can be personalized with any photo or theme for any occasion. NO EXTRA CHARGE FOR RUSH ORDERS OR CUSTOMIZATION
Promotional MerchandiseBusiness Promotional GiftsPromotional GiftsMarketing Products
Islip, NY
We are a design company dedicated to the embellishment of apparel, promo products and vinyl sign making for outdoor/indoor displays for windows, decals and cars
Corporate ApparelDecorated Apparel
Yellow page style directory and guide for shopping on Long Island NY. Major malls and shopping centers organized by Long Island towns, and business areas
Beautiful & Sweet is a custom home video editing service. We will edit your home movies at an affordable price. Your montage can be completely customized to suit your needs and wants. You give us the footage, photos,…
Coram, NY
joeyank.com We have brand names items at a great discount price
Wedding Gift IdeasAnniversary GiftsOnline GiftsGifts For Men
Port Jefferson Station, NY
We participate in craft and gift shows across Long Island
Personalized Gift IdeaPersonalized Child GiftCeramic PlatesMugs
Farmingville, NY
Golf ItemsPromotional GiftsMarketing ProductsPersonalized Pens
Riverhead, NY
Custom T ShirtsPersonalized Baby BlanketsEmbroidered Polo ShirtsEmbroidered Shirts
Can't find Personalized Gifts company near near Suffolk NY? Let us know by adding the missing business here.
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One of two men who robbed two convenience stores in April and then shot at police during a high-speed chase on valley streets and freeways was sentenced to 15 to 50 years in prison Thursday.
Richard Anthony Sanchez, 20, in October pleaded guilty to five felony counts in two separate cases, including attempted murder and armed robbery.
In August, Sanchez's co-defendant, Kyle Knights, 18, pleaded guilty to three counts and was sentenced to six to 20 years in prison.
Sanchez and Knights were arrested about 2 a.m. April 27 after officers performed a maneuver to spin and stall their truck on U.S. Highway 95 near Eastern Avenue. The defendants suffered minor injuries and were treated at a hospital.
Authorities said that Knights was driving and that Sanchez, the passenger, fired about eight shots at pursuing officers. None of the officers was injured.
Authorities said the two men robbed the Rebel convenience store at 4220 E. Sahara Ave. and the Green Valley Grocery store at 5785 E. Charleston Blvd .
Sanchez's criminal history includes arrests on allegations of assault, attempted murder and drug trafficking.
Contact reporter Francis McCabe at email@example.com or 702-380-1039.