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Several lines of evidence have suggested the importance of ET-1 in chronic hypoxic pulmonary hypertension. ET-1 is increased in plasma and lungs of rats following exposure to hypoxia [80, 97] . Treatment with either ETA or combined ETA and ETB receptor antagonists additionally attenuates the development of hypoxic pulm... |
ET-1 has also been implicated in other animal models of pulmonary hypertension. ET-1 is increased in fawn hooded rats that develop severe pulmonary hypertension when raised under conditions of mild hypoxia and in monocrotaline treated rats [101, 102] . The increase in ET-1 in both of these forms of pulmonary hypertensi... |
Human pulmonary hypertension is classified as primary, or unexplained, or secondary to other cardiopulmonary diseases or connective tissue diseases (ie scleroderma). Hallmarks of the disease include progressive increases in pulmonary vascular resistance and pulmonary vascular remodeling, with thickening of the medial l... |
Several lines of evidence suggest the importance of ET-1 in lung allograft survival and rejection. The peptide has been implicated as an important factor in ischemia-reperfusion injury at the time of transplant as well as in acute and chronic rejection of the allograft. |
Circulating ET-1 is increased in humans undergoing lung transplant immediately following perfusion of the allograft. Plasma ET-1 increased threefold within minutes, remained high for 12 hours following transplantation, and declined to near normal levels within 24 hours [113] . This increase in ET-1 correlated with the ... |
The cellular source of ET-1 in lung allografts is unknown. The expression of ET-1 in nontransplanted human lungs is low and found primarily in the vascular endothelium [114] . Transbronchial biopsy specimens obtained either for surveillance or for clinical suspicion of infection or rejection following transplantation r... |
Analysis of ET-1 binding activity in failed transplanted human lungs suggested that ET-1 binding activity was not different compared with normal lung in the lung parenchyma, bronchial smooth muscle, or perivascular infiltrates. ET-1 binding was, however, decreased in small muscular arteries (pulmonary arteries and bron... |
Ischemia-reperfusion injury is the leading cause of early post-operative graft failure and death. In its severest manifestation, increased pulmonary vascular resistance, hypoxia, and pulmonary edema lead to cor pulmonale and death [118] . ET-1 has been implicated as a mediator of these events. The increase in pulmonary... |
Acute rejection is manifested by diffuse infiltrates, hypoxia, and airflow limitation, and may lead to respiratory insufficiency and death. BAL ET-1 was increased in dogs during episodes of acute rejection that decreased with immunosuppressive treatment [124] . Acute episodes of rejection in humans, however, are not as... |
The mitogenic effects of ET-1 may play a role in the development of pulmonary malignancy as well as metastasis to the lung. Many human tumor cell lines, including prostate, breast, gastric, ovary, colon, etc, produce ET-1. The importance of the ET-1 may lie in its mitogenic effects on tumor growth and survival. This ha... |
ET-1 has been detected using immunohistochemistry and in situ hybridization in pulmonary adenocarcinomas and squamous cell tumors and, to a lesser extent, small cell and carcinoid tumors [133] . In situ hybridization also demonstrated a similar pattern of ET-1 mRNA expression in non-neuroendocrine tumors. ET-1 receptor... |
Tumor angiogenesis is necessary for continued growth of the tumor beyond the limits of oxygen diffusion. The growth of vessels into the tumor is also important to metastatic potential of the tumor. ET-1 may play an important role in angiogenesis and tumor growth and survival Available online http://respiratory-research... |
Experimental lung injury of many different types results in increased circulating ET-1, BAL ET-1, and lung tissue ET-1 [18] . ET-1 levels in humans are also increased in sepsis, burns, disseminated intravascular coagulation, acute lung injury, and acute respiratory distress syndrome (ARDS) [141] [142] [143] [144] [145]... |
Another hallmark of ARDS is disruption and dysfunction of the pulmonary vascular endothelium leading to accumulation of lung water. The role of endothelin in formation of pulmonary edema is uncertain. Infusion of ET-1 raises pulmonary vascular pressure, but it is uncertain whether ET-1 by itself increased pulmonary pro... |
Pulmonary fibrosis is the final outcome for a variety of injurious processes involving the lung parenchyma. The final common pathway in response to injury to the alveolar wall involves recruitment of inflammatory cells, release of inflammatory mediators, and resolution. The reparative phase occasionally becomes disorde... |
ET-1 in the lung may be important in the initial events in lung injury by activating neutrophils to aggregate and release elastase and oxygen radicals, increasing neutrophil adherence, activating mast cells, and inducing cytokine production from monocytes [65] [66] [67] [68] [69] 149, 155] . Among the many cytokines in... |
Several lines of evidence regarding the importance of ET-1 in pulmonary fibrosis are available. Plasma and BAL ET-1 levels are increased in idiopathic pulmonary fibrosis [50, 165] . Lung biopsies from patients with idiopathic pulmonary fibrosis have additionally increased ET-1 immunostaining in airway epithelial cells ... |
While ET-1 seems to correlate with pulmonary fibrosis, it remains uncertain whether the increase in ET-1 is a cause or consequence of the lung disease. Pulmonary fibrosis was recently reported in mice that constitutively overexpress human ET-1 [107] . These mice were known to develop progressive nephrosclerosis in the ... |
Since its discovery 12 years ago, much evidence has accumulated regarding the biologic activity and potential role of ET-1 in a variety of diseases of the respiratory track. As compelling as much of this evidence is, the causal relationship between ET-1 activity and disease is not complete. The increasing use of ECE an... |
Most of our understanding of responses to pneumovirus infection has emerged from studies of RSV infection of human epithelial target cells in vitro; a list of genes and/or gene products produced by epithelial cells in response to RSV infection in vitro is provided in Table 1 . At the cellular level, epithelial cells in... |
are understood) of these specific responses, and discuss several novel strategies that may permit us to study the responses to RSV and PVM infection in a more coherent and systematic manner. |
Tristram et al [1] observed that explanted respiratory epithelial cells slow their ciliary beat frequency almost immediately after exposure to RSV, with complete ciliostasis seen as early as 6 h after the initial infection. The molecular basis of ciliostasis remains completely unknown. |
The chemokines and cytokines with production and release that has been associated with RSV infection of human epithelial cells are listed in Table 1 . Much of this work was also recently reviewed elsewhere [2, 3] . We focus here on the three chemokines whose molecular mechanisms and physiologic implications are best un... |
The earliest reports on this subject described production of the neutrophil chemoattractant IL-8 from tissue culture supernatants from RSV-infected cells [4] [5] [6] and in nasal secretions from patients with viral rhinitis [7] . IL-8 has since been detected in lower airway secretions from patients with severe RSV bron... |
At the cellular level IL-8 production can be observed in response to inactivated RSV virions, whereas IL-8 production in response to active infection was inhibited by ribavarin, amiloride, and antioxidants [9, 10] . Several groups have demonstrated activation of the transcription factor nuclear factor-κB (NF-κB) in res... |
The pleiotropic chemokine regulated upon activation, normal T-cell expressed and secreted (RANTES) has also been detected in supernatants from RSV-infected epithelial cells in culture [17, 18] , as well as in upper and lower airway secretions from patients infected with this virus [7, 8] . RANTES acts as a chemoattract... |
Several groups have recently shown that macrophage inflammatory protein (MIP)-1α is released from RSVinfected cells in culture [7, 21] ; MIP-1α was also detected in upper and lower airway secretions from RSV-infected patients [7, 8] . Interestingly, of the three aforementioned chemokines, MIP-1α is the one that is most... |
A list of cell-surface molecules that have been reported as expressed in response to RSV infection is shown in Table 1 . We focus here on the expression of intercellular adhesion molecule (ICAM)-1 (CD54) and the leukocyte integrin CD18. |
Increased expression of this cell-surface adhesion protein was observed in both respiratory epithelial cell lines [23, 24] and in human nasal epithelial cells [25] in response to infection with RSV in vitro. Chini et al [26] demonstrated that the expression of ICAM-1 mRNA, similar to IL-8 and RANTES, was dependent on a... |
CD18 is a polypeptide of the integrin family that functions in mediating cell-cell interactions. Several groups have observed expression of CD18 on epithelial cells in response to RSV infection [27, 28] , with CD18 shown to enhance the degranulation of eosinophils in this specific setting [28] . Of particular interest ... |
Two more recent studies addressed the question of binding sites. Saadi et al [31] determined that two strains of the pathogen Bordetella pertussis bound more efficiently to RSV-infected cells, and that the binding was reduced upon pretreatment of the cells with anti-CD14 or anti-CD18 antibodies. Similarly, Raza et al [... |
RSV-infected epithelial cells in culture do not show features that are suggestive of apoptosis (ie no evidence of membrane blebbing, fragmentation of chromosomal DNA, or characteristic changes in nuclear morphology). Takeuchi et al [33] showed that, although RSV-infected epithelial cells express a number of apoptosis-a... |
As part of our attempts to understand mucosal responses in a more systematic manner (see below), we discovered that RSV-infected epithelial cells express the recently described antiapoptosis gene IEX-1L [34] . In our studies, we found that expression of IEX-1L is a response to active virus; no gene expression was obser... |
Apoptosis is generally considered to be a highly efficient self-defense mechanism employed by host target cells, because it permits the infected host to dispose of viral proteins and nucleic acids on a single-cell basis without inducing an inflammatory response. It is thus not surprising that many viruses have evolved ... |
Although virus-induced protection from apoptosis appears advantageous to the virus alone, another interpretation may be considered. Because respiratory epithelial cells are now recognized as a major source of leukocyte chemoattractants, and because leukocyte recruitment to the lung has been associated with enhanced vir... |
Available online http://respiratory-research.com/content/2/4/225 |
In tissue culture, RSV-infection is characterized by the formation of giant-cell syncytia. The mechanisms for the formation of these fused masses of cells depend in part on the expression of the RSV-specific fusion (F) protein on the surface of infected host cells, and in part on virusmediated changes in cytoskeletal a... |
Again, as part of our systematic study of gene expression in response to pneumovirus infection, we found that human respiratory epithelial cells respond to RSV infection with increased expression of the cytoskeletal protein cytokeratin-17 [36] . Cytokeratin-17 is a 46-kDa cytoskeletal protein that belongs to the class ... |
To date, efforts to study pneumovirus-induced alterations in gene expression have relied heavily on in vitro models of virus-infected cells and cell lines. The intrinsic value of characterizing the genes identified in this artificial system is by definition limited, and the clinical and physiologic sig-nificance of any... |
To some extent, the study of gene products in clinical specimens is possible, but this approach is limited, cumbersome, and dictated by sample availability. It is clear that an appropriate animal model of inflammatory bronchiolitis is required to characterize the alterations in gene expression discovered using the avai... |
To begin, we described the cellular and biochemical pathology observed in response to PVM infection in mice [38] . We found that infection could be established with as few as 30 plaque-forming units (pfu) of PVM in the inoculum, with infection resulting in significant morbidity and mortality, and viral recoveries in th... |
We also described the role played by MIP-1α in the pathogenesis of PVM-induced bronchiolitis [22] . Specifi- cally, we explored the responses of gene-deleted mice to infection with PVM, and found no inflammatory response in mice deficient in MIP-1α expression (MIP-1α -/-) and only minimal virus-induced inflammation in ... |
Our most recent report on this subject [39] presents a direct comparison between the responses of mice to challenge with PVM and RSV. Although RSV is not a natural pathogen of mice, it has been used extensively in mouse models of human infection because a limited, or 'semipermissive' infection can be established via in... |
Taken together, our results suggest that infection of mice with PVM provides a superior model for the study of acute inflammatory bronchiolitis in response to pneumovirus infection in vivo. The advantages of this model include the following: clinical parameters -morbidity and mortalitythat can be measured clearly and s... |
Traditionally, analysis of gene expression through measurement of steady-state levels of individual mRNAs could be conducted only one gene at a time using northern blotting, dot blots, or quantitative reverse transcription-PCR. Differential display, serial analysis of gene expression, and total gene analysis offer grea... |
Differential display is a semiquantitative, reverse transcription-PCR-based technique that is used to compare mRNAs from two or more conditions of interest. Both increased and decreased expression of specific amplicons will be evident -an obvious advantage to this approach. Total RNA can be isolated from virus infected... |
The DNA sequences of the newly identified differentially expressed amplicons are compared with sequences present in the GenBank database. Viral sequences are expected to be upregulated over time and can be identified immediately, because the entire genomes of both PVM and RSV are present in GenBank. In cases in which t... |
With the help of differential display, we have identified and characterized several genes that are upregulated in RSV-infected respiratory epithelial cells. Two specific examples of genes that were found to be induced during RSV infection, and later characterized as playing independent roles in the pathophysiology of R... |
Unlike DNA viruses, which are known to encode virus-specific antiapoptosis genes, RSV -an RNA virus with a small (approximately 15.2 kb) viral genome -was shown to alter host cell expression of the apoptosis inhibitor IEX-1L. After demonstrating that IEX-1L mRNA was present at sevenfold higher concentrations in RSV-inf... |
A second example of a gene that is specifically upregulated in RSV-infected respiratory epithelium, as identified by differential display, is that which encodes cytokeratin-17 [36] . Upon characterizing the molecular events that are important for cytokeratin-17 induction, we demonstrated a link to an NF-κB signaling pa... |
Although there are several companies that market these systems and components, the cytokine gene macroarray systems recently developed by R&D Systems (Sigma Genosys ® ; Minneapolis, MN, USA) and Clontech (Atlas ® ; Palo Alto, CA, USA) represent some of the newer opportunities available that have a focus on gene product... |
The resulting radiolabeled products were hybridized to the macroarrays overnight at 65°C, and then washed and exposed to film. The arrow highlights one of the most obviously upregulated sequences from this experiment, which was identified as the gene encoding human MIP-1α. The physiologic importance of MIP-1α upregulat... |
Microarrays can be differentiated from macroarrays in several ways. Among these differences, the microarray matrix is a glass or plastic slide, probes are labeled with fluorescent dye rather than via radioisotopes, and, most significantly, microarrays generally include a larger number and a higher density of imbedded s... |
The pneumoviruses RSV and PVM enter respiratory epithelial cells via a receptor-mediated event. During hostcell attachment and internalization, the target cell begins to alter its gene expression, which, among other events, involves the transcriptional upregulation of cytokine and chemokine genes. As RSV replication pr... |
genomic approaches as large-scale screening tools to identify genes that play important roles in the pathophysiology of pneumovirus infection. These elegant and simple tools will provide us with the means for thorough and systematic exploration of gene expression, both in the estab- Cytokine macroarray probed with radi... |
Some viruses, such as brome mosaic virus, initiate sg mRNA synthesis internally on the full-length minus strand RNA template (Miller et al., 1985) . Others, exempli®ed by red clover necrotic mosaic virus (RCNMV), may rely on premature termination of minus strand synthesis from the genomic RNA template, followed by the ... |
Various models have been put forward to explain the cotranscriptional fusion of non-contiguous parts of the nidovirus genome during sg RNA synthesis ( Figure 1B and C). Central to each of these models are short transcription-regulating sequences (TRSs), which are present both at the 3¢ end of the leader and at the 5¢ e... |
Sequence requirements for RNA strand transfer during nidovirus discontinuous subgenomic RNA synthesis The EMBO Journal Vol. 20 No. 24 pp. 7220±7228, 2001 Using site-directed mutagenesis of TRSs of the arterivirus equine arteritis virus (EAV), we have shown previously that base pairing between the sense leader TRS and a... |
To gain further insight into the cis-acting signals regulating sg RNA synthesis, we performed a comprehensive site-directed mutagenesis study of the EAV leader and body TRSs. Every nucleotide of the TRS (5¢-UCAACU-3¢) was substituted with each of the three alternative nucleotides. Our analysis revealed a number of stri... |
EAV genome replication is not signi®cantly affected by leader TRS and body TRS mutations To dissect EAV RNA synthesis, we routinely use a fulllength cDNA clone (van Dinten et al., 1997) , from which infectious EAV RNA is in vitro transcribed. Following transfection of the RNA into baby hamster kidney (BHK-21) cells, in... |
The three mutants were tested in three independent experiments. Intracellular RNA was isolated at 14 h posttransfection, early enough to prevent spread of the wildtype control virus to non-transfected cells (®rst cycle analysis). Transfection ef®ciencies were determined by immuno¯uorescence assays (see Materials and me... |
The RNA±RNA interaction between the leader and body TRSs is not the only factor that regulates EAV sg RNA synthesis There are numerous examples of regulatory RNA±RNA interactions in both eukaryotic and prokaryotic cells, as well as in RNA viruses. Essential processes such as translation, replication and encapsidation o... |
Recently, we have established the pivotal role of an interaction between sense and antisense RNA sequences in the life cycle of EAV (van Marle et al., 1999a) . In that study, the role of TRS nucleotides C 2 and C 5 was tested by substituting them with G. It was concluded that base pairing between the sense leader TRS a... |
The comprehensive analysis of the effects of TRS mutations considerably expanded our understanding of van Dinten et al., 1997) was taken along as a positive control. For every mutant, the level of sg RNA7 synthesis was calculated as [(sg/g)/(sg/g) wt ] 3 100%: it was corrected for the level of genomic RNA (used as an i... |
A.O. Pasternak et al. discontinuous sg RNA synthesis. Remarkably, the effects of single (leader or body) TRS mutations were mostly base speci®c, i.e. different nucleotide substitutions at the same position affected sg RNA7 synthesis to different extents. For example, at position 1, the BU 1 A mutant retained 44% of the... |
Differentiating between effects at the level of primary TRS sequence and the level of leader±body duplex formation For some TRS nucleotides (2, 5 and 6, except in the case of DU 6 C), the RNA7 level of double mutants was clearly higher than that of the corresponding single mutants. This means that base pairing between ... |
Body TRS mutants thus fell into two distinct types, determined by the position and chemistry of the substitution. In mutants of the ®rst type, sg RNA synthesis was impaired mainly because of the disruption of the leader± body TRS duplex. This effect could be compensated for by introduction of the corresponding mutation... |
In contrast to our ®ndings with the body TRS mutants, we did not obtain leader TRS mutations that appeared to determine the level of sg RNA7 synthesis of the corresponding double mutant (Figure 3) . Thus, effects of mutations in the leader TRS were not`dominant' over the duplex-restoring effects of the double mutations... |
The observation that leader TRS mutations could bè rescued' by introducing complementary mutations in the body TRS, but that many body TRS mutations could not bè rescued' by corresponding changes in the leader TRS, is clearly illustrated by the U 1 A mutants. Due to the restoration of TRS base pairing possibilities, th... |
These results indicate that there are strong base preference constraints for some body TRS positions. To interpret these base preferences accurately, it is necessary to limit the analysis to the double mutants only, because in these mutants the down-regulation of sg RNA synthesis was only due to the sequence changes in... |
Until recently (Almazan et al., 2000; Thiel et al., 2001) , infectious cDNA clones were lacking for coronaviruses. Consequently, most studies on coronavirus sg RNA synthesis were carried out using defective interfering (DI) RNAs. These replicons carried body TRSs from which moderate levels of sg mRNAs could be produced... |
In a similar study, van der Most et al. (1994) observed that U to C substitutions at positions 1 and 3 of the MHV body TRS, which maintained the duplex by changing a U±A base pair into a U±G base pair, reduced sg RNA levels more strongly than substitutions that disrupted the duplex (van der Most et al., 1994) . This im... |
The discontinuous step in nidovirus sg RNA synthesis occurs during minus strand RNA synthesis Due to recent studies of arterivirus and coronavirus sg RNA synthesis (van Marle et al., 1999a; Baric and Yount, 2000; Sawicki et al., 2001) , the discontinuous minus strand extension model ( Figure 1C ) has been gaining more ... |
Using the same approach, we analysed mRNA7 from mutants BC 2 A and BC 2 U, and these transcripts also contained the mutated nucleotide derived from the body TRS (data not shown). Assuming that only one crossover event occurs during leader±body joining, we could thus map this crossover between positions ±1 and +2 of the... |
Using the position 1 mutants described above, we could answer this question ( Figure 5) . The most striking result was that mRNA7 of mutants BU 1 A, BU 1 G and LU 1 C contained exclusively the body TRS-derived nucleotide at position +1. Thus, for these mutants, the crossover site could be mapped precisely between TRS n... |
We believe that our present ®ndings strongly support the discontinuous minus strand extension model. Indeed, the fact that a complete body TRS can be copied into the sg RNA is very dif®cult to reconcile with the alternative model, in which sg RNA synthesis from the genomic minus strand template is primed by free plus s... |
Removal of the TRS at the 3¢ end of the nidovirus leader, which has already base paired with the template, would be very energetically unfavourable for the RdRp. Instead of starting elongation using the intact and properly positioned leader as a primer, it would have to disrupt the newly formed duplex, degrade part of ... |
Sequence data of sg RNA leader±body junctions from other arteriviruses are also dif®cult to reconcile with the leader-primed transcription model. For the porcine and simian arteriviruses (Meulenberg et al., 1993; Godeny et al., 1998) , the leader±body junctions of some sg RNAs mapped two nucleotides upstream of the bod... |
Nidovirus discontinuous minus strand extension resembles similarity-assisted, copy-choice RNA recombination Due to their discontinuous sg RNA synthesis, nidoviruses occupy a special`niche' in the +RNA virus world. Their mode of sg RNA production is clearly different from that of other +RNA viruses and resembles another... |
Based on the data currently available, we refer to the discontinuous minus strand extension model as our working model for nidovirus sg RNA synthesis. If one applies the`recombination terms' to this model (Chang et al., 1996; Brian and Spaan, 1997; van Marle et al., 1999a) , the donor strand would be the body part of t... |
The results of our present study strongly suggest that nidovirus discontinuous sg RNA synthesis can be considered a special case of high-frequency similarity-assisted RNA recombination. While the only obvious function of the leader TRS is to ensure the ®delity of the strand transfer by base pairing with the 3¢ end of t... |
RNA secondary structure of the body TRS may regulate sg RNA synthesis The sequence-speci®c function of the body TRS, revealed in this study, may be exerted at the level of either primary sequence or secondary structure. For a number of +RNA viruses, RNA secondary structure motifs located in the (proximity of) sg RNA pr... |
We have suggested previously that RNA secondary structure of body TRS regions contributes to their attenuating potential and thereby determines the relative portion of the nascent minus strands that is transferred to the leader TRS in the template (Pasternak et al., 2000) . At present, it is unknown whether EAV body TR... |
In the TCV satellite RNA recombination system, the hairpin structure in the acceptor strand, as well as the donor±acceptor homology region, are necessary for the template switch . The hairpin has been postulated to bind the RdRp, whereas the homology region targets the nascent strand to the crossover site. The TCV RdRp... |
The body TRS is a better candidate to serve as a protein recognition site. This protein would then mediate the pausing of the nascent strand synthesis and/or nascent strand transfer. This would resemble the DNA-dependent RNA polymerase I termination system, in which speci®c DNA-binding terminator proteins bind to termi... |
Site-directed mutagenesis, RNA transfections and immuno¯uorescence analysis Site-directed mutagenesis of EAV leader and body TRSs was carried out as described by van Marle et al. (1999a) , and all mutant constructs were sequenced. Following in vitro transcription from infectious cDNA clones, full-length EAV RNA was int... |
For RNA analyses, cells were lysed at 14 h post-transfection. Intracellular RNA isolation was performed using the acidic phenol method as described by Pasternak et al. (2000) . Total intracellular RNA was resolved in denaturing agarose±formaldehyde gels. Hybridization of dried gels with the radioactively labelled oligo... |
It is the aim of the present commentary to justify the statement 'Transfusing to normal haemoglobin concentration will not improve outcome.' If we define normal haemoglobin as being greater than 115 g/l for women and greater than 125 g/l for men, then there is no evidence in the literature to justify maintaining such h... |
RBC transfusions have inherent risks that may be categorized as follows [11] [12] [13] [14] [15] : transfusion-transmitted infections; immune-related reactions (acute or delayed haemolytic reactions, febrile, allergic, anaphylactic reactions and graft-versus-host disease); and nonimmunerelated reactions (fluid overload... |
Major improvements in donor screening procedures and laboratory testing have dramatically improved the safety of the blood supply [16] . Currently, the risk of transmitting an infectious agent through blood transfusion ranges from 1:100,000 for hepatitis B virus to 1:1,000,000 for HIV (Canadian Blood Services, personal... |
It is a long-standing observation [17] [18] [19] [20] [21] that blood transfusions are associated with immune suppression. This clinical phenomenon was first observed in renal transplant patients who had received blood transfusions while on dialysis before the transplant [22] , and has been observed repeatedly in trans... |
A large number of studies [26] [27] [28] [29] [30] [31] [32] [33] [34] have also suggested that allogeneic transfusions accelerate cancer growth, perhaps due to altered immune surveillance. These altered immune responses after allogeneic RBC transfusions may also predispose critically ill transfusion recipients to noso... |
A recent meta-analysis [44] combined the results from seven RCTs, and was unable to detect clinically important decreases in mortality and postoperative infections. We added the results of a new RCT by van de Watering et al [45] to the above meta-analysis. The relative risk for allcause mortality was 1.05 (95% confiden... |
The majority of complications from allogeneic RBC transfusion, however, are no more frequent in the intensive care setting than in other patient populations, with the possible exception of pulmonary oedema, hypothermia and electrolyte disturbance. Hypothermia and electrolyte disturbances occur most frequently with mass... |
Clinical evidence is also insufficient to definitively establish a correlation between the age of RBCs being transfused and patient mortality; however, laboratory evidence has shown many storage-related changes that may result in impairment of blood flow and oxygen delivery at the microcirculatory level. Marik et al [4... |
Three retrospective clinical studies tested the association between the age of transfused blood and duration of stay in the intensive care unit (ICU) [50] and mortality [51, 52] . Martin et al [50] observed a statistically significant association between the transfusion of aged blood (>14 days old) and increased durati... |
Until recently, physicians have depended on clinical judgement when deciding at what haemoglobin level to transfuse a critically ill patient. As a result, significant variation has been shown to exist in transfusion practice among Canadian critical care physicians [53] , which is due largely to a lack of published data... |
Six observational studies investigated the importance of anaemia on transfusion practices in various settings. Of these, three large cohort studies, which were performed in different patient populations (intensive care [1] , coronary artery bypass surgery [54] and hip fractures [55]), reached different conclusions. RBC... |
Transfusion thresholds were compared in 10 randomized clinical trials [10, [59] [60] [61] [62] [63] [64] [65] [66] [67] . Although the clinical settings varied, each trial randomized patients to be transfused on the basis of a 'conservative' or a 'liberal' strategy. The definitions of conservative and liberal strategie... |
In 1999, Hebert et al [10] reported the results of the TRICC trial. Patients (n = 838) were randomized either to a restrictive strategy (haemoglobin concentration maintained between 70 and 90 g/l, with a trigger set at 70 g/l) or to a liberal strategy (haemoglobin concentration maintained between 100 and 120 g/l, with ... |
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