Dalteparin versus unfractionated heparin in critically ill patients.

BACKGROUND: The effects of thromboprophylaxis with low-molecular-weight heparin, as compared with unfractionated heparin, on venous thromboembolism, bleeding, and other outcomes are uncertain in critically ill patients. METHODS: In this multicenter trial, we tested the superiority of dalteparin over unfractionated heparin by randomly assigning 3764 patients to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated. Additional testing for venous thromboembolism was performed as clinically indicated. Data were analyzed according to the intention-to-treat principle. RESULTS: There was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P=0.57). The proportion of patients with pulmonary emboli was significantly lower with dalteparin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%) (hazard ratio, 0.51; 95% CI, 0.30 to 0.88; P=0.01). There was no significant between-group difference in the rates of major bleeding (hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P=0.98) or death in the hospital (hazard ratio, 0.92; 95% CI, 0.80 to 1.05; P=0.21). In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced thrombocytopenia (hazard ratio, 0.27; 95% CI, 0.08 to 0.98; P=0.046). CONCLUSIONS: Among critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. (Funded by the Canadian Institutes of Health Research and others; PROTECT ClinicalTrials.gov number, NCT00182143.).

Vascular endothelial growth factor A (VEGF-A) induces endothelial and cancer cell migration through direct binding to integrin {alpha}9{beta}1: identification of a specific {alpha}9{beta}1 binding site.

Integrin α9ß1 mediates accelerated cell adhesion and migration through interactions with a number of diverse extracellular ligands. We have shown previously that it directly binds the vascular endothelial growth factors (VEGF) A, C, and D and contributes to VEGF-induced angiogenesis and lymphangiogenesis. Until now, the α9ß1 binding site in VEGF has not been identified. Here, we report that the three-amino acid sequence, EYP, encoded by exon 3 of VEGF-A is essential for binding of VEGF to integrin α9ß1 and induces adhesion and migration of endothelial and cancer cells. EYP is specific for α9ß1 binding and neither requires nor activates VEGFR-2, the cognate receptor for VEGF-A. Following binding to EYP, integrin α9ß1 transduces cell migration through direct activation of the integrin signaling intermediates Src and focal adhesion kinase. This interaction is biologically important because it mediates in vitro endothelial cell tube formation, wound healing, and cancer cell invasion. These novel findings identify EYP as a potential site for directed pharmacotherapy.

Impact of Pharmacologically Left Shifting the Oxygen-Hemoglobin Dissociation Curve on Arterial Blood Gases and Pulmonary Gas Exchange During Maximal Exercise in Hypoxia.

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. High Alt Med Biol. 22:249-262, 2021. Introduction: Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO2) and exercise capacity. Methods: Eight healthy subjects completed a maximal incremental exercise test in hypoxia (FIO2: 0.125) and normoxia (FIO2: 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort (n = 3). Results: Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg, p < 0.05). Throughout incremental exercise in hypoxia, SaO2 was systematically higher after drug (peak exercise SaO2 on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%, p < 0.001), whereas oxygen extraction (Ca-vO2 diff) and consumption (VO2) were similar (peak exercise Ca-vO2 diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood, p = 0.417; peak VO2 on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min, p = 0.127). Throughout incremental exercise in normoxia, SaO2 was systematically higher after drug, whereas peak VO2 was reduced (peak exercise SaO2 on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%, p = 0.008; peak VO2 on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min, p = 0.001). Conclusion: Pharmacologically increasing the affinity of Hb for oxygen improved SaO2 during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.

Vascular endothelial growth factors C and D induces proliferation of lymphangioleiomyomatosis cells through autocrine crosstalk with endothelium.

Lymphangioleiomyomatosis (LAM) is a potentially fatal lung disease characterized by nodules of proliferative smooth muscle-like cells. The exact nature of these LAM cells and their proliferative stimuli are poorly characterized. Herein we report the novel findings that the lymphangiogenic vascular endothelial growth factors (VEGF) C and D induce LAM cell proliferation through activation of their cognate receptor VEGF-R3 and activation of the signaling intermediates Akt/mTOR/S6. Furthermore, we identify expression of the proteoglycan NG2, a marker of immature smooth muscle cells, as a characteristic of LAM cells both in vitro and in human lung tissue. VEGF-C-induced LAM cell proliferation was in part a result of autocrine stimulation that resulted from cross talk with lymphatic endothelial cells. Ultimately, these findings identify the lymphangiogenic VEGF proteins as pathogenic growth factors in LAM disease and at the same time provide a novel pharmacotherapeutic target for a lung disease that to date has no known effective treatment.

Effects of an allosteric hemoglobin affinity modulator on arterial blood gases and cardiopulmonary responses during normoxic and hypoxic low-intensity exercise.

Numerous pathophysiological conditions induce hypoxemia-related cardiopulmonary perturbations, decrements in exercise capacity, and debilitating symptoms. Accordingly, this study investigated the efficacy of an allosteric hemoglobin modulator (voxelotor) to enhance arterial oxygen saturation during low-intensity exercise in hypoxia. Eight normal healthy subjects (36 ± 7 yr; 73.8 ± 9.5 kg; 3 women) completed a submaximal cycling test (60 W) under normoxic ([Formula: see text]: 0.21; O2 partial pressure: 144 mmHg) and hypoxic ([Formula: see text]: 0.125; O2 partial pressure: 82 mmHg) conditions before (day 1) and after (day 15) 14 days of oral drug administration. While stationary on a cycle ergometer and during exercise, ratings of perceived exertion (RPE) and dyspnea, oxygen consumption (V̇o2), and cardiac output (Q) were measured noninvasively, while arterial blood pressure (MAP) and blood gases ([Formula: see text], [Formula: see text], and [Formula: see text]) were measured invasively. The 14-day drug administration left shifted the oxygen-hemoglobin dissociation curve (ODC; p50 measured at standard pH and Pco2; day 1: 28.0 ± 2.1 mmHg vs. day 15: 26.1 ± 1.8 mmHg, P < 0.05). RPE, dyspnea, V̇o2, Q, and MAP were not different between day 1 and day 15. [Formula: see text] was similar during normoxia on day 1 and day 15 while stationary but higher during exercise (day 1: 95.2 ± 0.4% vs. day 15: 96.6 ± 0.3%, P < 0.05). [Formula: see text] was higher during hypoxia on day 15 while stationary (day 1: 82.9 ± 3.4% vs. day 15: 90.9 ± 1.8%, P < 0.05) and during exercise (day 1: 73.6 ± 2.5% vs. day 15: 84.8 ± 2.7%, P < 0.01). [Formula: see text] and [Formula: see text]were systematically higher and lower, respectively, after drug (P < 0.01), while the alveolar-arterial oxygen difference was unchanged suggesting hyperventilation contributed to the rise in [Formula: see text]. Oral administration of voxelotor left shifted the ODC and stimulated a mild hyperventilation, leading to improved arterial oxygen saturation without altering V̇o2 and central hemodynamics during rest and low-intensity exercise. This effect was more pronounced during submaximal hypoxic exercise, when arterial desaturation was more evident. Additional studies are needed to determine the effects of voxelotor during maximal exercise and under chronic forms of hypoxia.NEW & NOTEWORTHY In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity state during submaximal exercise in normoxia and hypoxia. Oral administration of voxelotor enhanced arterial oxygen saturation during submaximal exercise without altering oxygen consumption and central hemodynamics; however, the partial pressure of arterial carbon dioxide was reduced and the partial pressure of arterial oxygen was increased implying that hyperventilation also contributed to the increase in oxygen saturation. The preservation of arterial oxygen saturation and content was particularly evident during hypoxic submaximal exercise, when arterial desaturation typically occurs, but this did not influence arterial-venous oxygen difference.

Fetal outcomes of critically ill pregnant women admitted to the intensive care unit for nonobstetric causes.

INTRODUCTION: The outcome of the fetus in critically ill mothers has been briefly reported as a part of descriptive studies focusing on maternal risk factors for admission to the intensive care unit. We evaluated the risk factors for adverse fetal outcomes in critically ill pregnant women admitted to the intensive care unit for nonobstetrical reasons. DESIGN: Retrospective cohort study of all critically ill pregnant patients >18 yr; admitted to four (medical, surgical, trauma, and mixed medical-surgical) intensive care units at the Mayo Clinic in Rochester, MN; during the period of January 1995 to December 2005. Only pregnant women admitted to the intensive care unit in the antepartum period for nonobstetrical indications were included. Main predictors for fetal outcomes included: maternal comorbidities, obstetrical history, intensive care unit interventions, and intensive care unit complications. Fetal outcomes were defined as spontaneous abortions, neonatal mortality, fetal deaths, admission to the neonatal intensive care unit, neonatal intensive care unit length of stay, and neonatal intensive care unit complications. RESULTS: A total of 153 adult women (>18 yr) with a diagnosis of pregnancy were admitted to the intensive care unit, of whom 93 pregnant women met the inclusion criteria. Median maternal age was 26 yr (interquartile range 22-33) and median gestational age was 25 wk (interquartile range 8-33). The median maternal Acute Physiologic and Chronic Health Evaluation III score was 27 (interquartile range 17-38). There were 32 fetal losses; 18 were spontaneous abortions and 14 were fetal deaths. Ten neonates required neonatal intensive care unit admission, five for respiratory distress syndrome; and only one neonate died. The median neonatal intensive care unit length of stay was 34 days (interquartile range 15-87). After multivariable logistic regression analysis, the risk factors associated with fetal loss were: presence of maternal shock, odds ratio 6.85 (95% confidence interval 1.16-58, p = 0.04); maternal transfusion of blood products, odds ratio 7.24 (95% confidence interval 1.4-49, p = 0.02); and gestational age, odds ratio 1.2 for every gestational week below 37 wk (95% confidence interval 1.1-1.3, p < 0.001). CONCLUSIONS: Nonobstetrical critical illness in pregnant women significantly affects fetal and neonatal outcomes. Maternal shock, maternal requirement of allogenic blood product transfusion and lower gestational age were associated with an increased risk of fetal loss.

Sirolimus-associated diffuse alveolar hemorrhage.

Sirolimus is an immunosuppressive medication used in transplant recipients. To our knowledge, we describe the third reported case of alveolar hemorrhage in association with sirolimus. Fever, dyspnea, hemoptysis, and lung infiltrates resolved rapidly with cessation of sirolimus therapy both initially and after reinstitution of the drug. Unlike previous reports, our patient had no evidence of lymphocytic alveolitis but rather marked macrophage hemosiderosis, suggesting that sirolimus pulmonary toxicity may manifest through 2 separate mechanisms. Our case highlights an uncommon but potentially lethal manifestation of sirolimus pulmonary toxicity.

Osteoarticular infection complicating enterococcal endocarditis.

Despite the common occurrence of musculoskeletal complaints in patients with infective endocarditis, infectious osteoarticular complications are diagnosed infrequently. Moreover, although enterococcal infection is the third most common cause of infective endocarditis, infectious osteoarticular complications are rare. We report a case of disk space infection in a patient with enterococcal endocarditis. Blood cultures and an L3-4 aspirate grew Enterococcus faecalis, and transthoracic echocardiography revealed a large vegetation on the posterior mitral valve leaflet. The osteoarticular infection resolved with antimicrobial treatment, but worsening heart failure necessitated valve replacement surgery. The patient had an uneventful recovery with no evidence of recurrence or complications. A review of the medical literature from 1966 through 1998 identified 13 additional cases, only 8 of which provided clinical and treatment data. We present the clinical and laboratory findings reported in these cases, along with data from our patient. This report highlights the rare occurrence of osteoarticular infection in the setting of enterococcal endocarditis and emphasizes early recognition and treatment.

Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study.

IMPORTANCE: Critically ill patients are at risk of venous thrombosis, and therefore guidelines recommend daily thromboprophylaxis. Deep vein thrombosis (DVT) commonly occurs in the lower extremities but can occur in other sites including the head and neck, trunk, and upper extremities. The risk of nonleg deep venous thromboses (NLDVTs), predisposing factors, and the association between NLDVTs and pulmonary embolism (PE) or death are unclear. OBJECTIVE: To describe the frequency, anatomical location, risk factors, management, and consequences of NLDVTs in a large cohort of medical-surgical critically ill adults. DESIGN, SETTING, AND PARTICIPANTS: A nested prospective cohort study in the setting of secondary and tertiary care intensive care units (ICUs). The study population comprised 3746 patients, who were expected to remain in the ICU for at least 3 days and were enrolled in a randomized clinical trial of dalteparin vs standard heparin for thromboprophylaxis. MAIN OUTCOMES AND MEASURES: The proportion of patients who had NLDVTs, the mean number per patient, and the anatomical location. We characterized NLDVTs as prevalent or incident (identified within 72 hours of ICU admission or thereafter) and whether they were catheter related or not. We used multivariable regression models to evaluate risk factors for NLDVT and to examine subsequent anticoagulant therapy, associated PE, and death. RESULTS Of 3746 trial patients, 84 (2.2%) developed 1 or more non-leg vein thromboses (superficial or deep, proximal or distal). Thromboses were more commonly incident (n = 75 [2.0%]) than prevalent (n = 9 [0.2%]) (P < .001) and more often deep (n = 67 [1.8%]) than superficial (n = 31 [0.8%]) (P < .001). Cancer was the only independent predictor of incident NLDVT (hazard ratio [HR], 2.22; 95% CI, 1.06-4.65). After adjusting for Acute Physiology and Chronic Health Evaluation (APACHE) II scores, personal or family history of venous thromboembolism, body mass index, vasopressor use, type of thromboprophylaxis, and presence of leg DVT, NLDVTs were associated with an increased risk of PE (HR, 11.83; 95% CI, 4.80-29.18). Nonleg DVTs were not associated with ICU mortality (HR, 1.09; 95% CI, 0.62-1.92) in a model adjusting for age, APACHE II, vasopressor use, mechanical ventilation, renal replacement therapy, and platelet count below 50 × 10(9)/L. CONCLUSIONS AND RELEVANCE Despite universal heparin thromboprophylaxis, nonleg thromboses are found in 2.2% of medical-surgical critically ill patients, primarily in deep veins and proximal veins. Patients who have a malignant condition may have a significantly higher risk of developing NLDVT, and patients with NLDVT, compared with those without, appeared to be at higher risk of PE but not higher risk of death. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00182143.

Heparin-induced thrombocytopenia in medical surgical critical illness.

BACKGROUND: In a recent multicenter randomized trial comparing unfractionated heparin (UFH) with low-molecular-weight heparin (dalteparin) for thromboprophylaxis in 3,746 critically ill patients, 17 patients (0.5%) developed heparin-induced thrombocytopenia (HIT) based on serotonin-release assay-positive (SRA+) status. A trend to a lower frequency of HIT with dalteparin vs UFH was observed in the intention-to-treat analysis (five vs 12 patients, P = .14), which was statistically significant (three vs 12 patients, P = .046) in a prespecified per-protocol analysis that excluded patients with DVT at study entry. We sought to characterize HIT outcomes and to determine how dalteparin thromboprophylaxis may reduce HIT frequency in patients in the ICU. METHODS: In 17 patients with HIT, we analyzed platelet counts and thrombotic events in relation to the study drug and other open-label heparin, to determine whether the study drug plausibly explained seroconversion to SRA+ status and/or breakthrough of thrombocytopenia/thrombosis. We also compared antibody frequencies (dalteparin vs UFH) in 409 patients serologically investigated for HIT. RESULTS: HIT-associated thrombosis occurred in 10 of 17 patients (58.8%) (8:1:1 venous:arterial:both). Dalteparin was associated with fewer study drug-attributable HIT-related events (P = .020), including less seroconversion (P = .058) and less breakthrough of thrombocytopenia/thrombosis (P = .032). Antiplatelet factor 4/heparin IgG antibodies by enzyme-linked immunosorbent assay were less frequent among patients receiving dalteparin vs UFH (13.5% vs 27.3%, P < .001). One patient with HIT-associated DVT died after UFH bolus (anaphylactoid reaction), whereas platelet counts recovered in two others with HIT-associated VTE despite continuation of therapeutic-dose UFH. CONCLUSIONS: The lower risk of HIT in patients in the ICU receiving dalteparin appears related to both decreased antibody formation and decreased clinical breakthrough of HIT among patients forming antibodies.

The induction of angiogenesis by cerium oxide nanoparticles through the modulation of oxygen in intracellular environments.

Angiogenesis is the formation of new blood vessels from existing blood vessels and is critical for many physiological and pathophysiological processes. In this study we have shown the unique property of cerium oxide nanoparticles (CNPs) to induce angiogenesis, observed using both in vitro and in vivo model systems. In particular, CNPs trigger angiogenesis by modulating the intracellular oxygen environment and stabilizing hypoxia inducing factor 1α endogenously. Furthermore, correlations between angiogenesis induction and CNPs physicochemical properties including: surface Ce(3+)/Ce(4+) ratio, surface charge, size, and shape were also explored. High surface area and increased Ce(3+)/Ce(4+) ratio make CNPs more catalytically active towards regulating intracellular oxygen, which in turn led to more robust induction of angiogenesis. Atomistic simulation was also used, in partnership with in vitro and in vivo experimentation, to reveal that the surface reactivity of CNPs and facile oxygen transport promotes pro-angiogenesis.

Integrin alpha9beta1: Unique signaling pathways reveal diverse biological roles.

Integrins are transmembrane heterodimeric receptors responsible for transducing and modulating signals between the extracellular matrix and cytoskeleton, ultimately influencing cell functions such as adhesion and migration. Integrin alpha9beta1 is classified within a two member sub-family of integrins highlighted in part by its specialized role in cell migration. The importance of this role is demonstrated by its regulation of numerous biological functions including lymphatic valve morphogenesis, lymphangiogenesis, angiogenesis and hematopoietic homeostasis. Compared to other integrins the signaling mechanisms that transduce alpha9beta1-induced cell migration are not well described. We have recently shown that Src tyrosine kinase plays a key proximal role to control alpha9beta1 signaling. Specifically it activates inducible nitric oxide synthase (iNOS) and in turn nitric oxide (NO) production as a means to transduce cell migration. Furthermore, we have also described a role for FAK, Erk and Rac1 in alpha9beta1 signal transduction. Here we provide an over view of known integrin alpha9beta1 signaling pathways and highlight its roles in diverse biological conditions.

Integrin alpha9beta1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase.

Integrins are important mediators of cell adhesion and migration, which in turn are essential for diverse biological functions, including wound healing and cancer metastasis. The integrin alpha9beta1 is expressed on numerous mammalian tissues and can mediate accelerated cell migration. As the molecular signaling mechanisms that transduce this effect are poorly defined, we investigated the pathways by which activated integrin alpha9beta1 signals migration. We found for the first time that specific ligation of integrin alpha9beta1 rapidly activates Src tyrosine kinase, with concomitant tyrosine phosphorylation of p130Cas and activation of Rac-1. Furthermore, activation of integrin alpha9beta1 also enhanced NO production through activation of inducible nitric oxide synthase (iNOS). Inhibition of Src tyrosine kinase or NOS decreased integrin-alpha9beta1-dependent cell migration. Src appeared to function most proximal in the signaling cascade, in a FAK-independent manner to facilitate iNOS activation and NO-dependent cell migration. The cytoplasmic domain of integrin alpha9 was crucial for integrin-alpha9beta1-induced Src activation, subsequent signaling events and cell migration. When taken together, our results describe a novel and unique mechanism of coordinated interactions of the integrin alpha9 cytoplasmic domain, Src tyrosine kinase and iNOS to transduce integrin-alpha9beta1-mediated cell migration.

Infective endocarditis due to community-associated methicillin-resistant Staphylococcus aureus in injection drug users may be associated with Panton-Valentine leukocidin-negative strains.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates that cause infective endocarditis in injection drug users (IDUs) are distinct from CA-MRSA strains that cause endocardial infection as a complication of skin and soft tissue infections. We present a case of CA-MRSA infective endocarditis, review pertinent cases previously published, and describe the molecular characteristics of strains from IDUs and patients with skin and soft tissue infections.

Six-month survival of patients with acute lung injury: prospective cohort study.

OBJECTIVE: Both short- and long-term outcome studies in acute lung injury (ALI) performed thus far were conducted before the implementation of recent advances in mechanical ventilation and supportive care and/or in the context of clinical trials with restricted inclusion criteria. We sought to determine the outcome of consecutive acute lung injury patients after the implementation of these interventions. DESIGN: Prospective cohort study. SETTING: Three intensive care units of two tertiary care hospitals. PATIENTS: Patients with acute lung injury treated from October 2005 to May 2006, excluding those with no research authorization or do-not-resuscitate order. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The investigators collected detailed information about comorbidities, severity of pulmonary and nonpulmonary organ failures, complications, respiratory support, and other interventions. The main outcome measure was mortality 6 months after the onset of acute lung injury. From 142 patients enrolled over a 6-month period, 24 (17%) died in the intensive care unit, 38 (27%) in the hospital, and 55 (39%) by the end of the 6-month follow-up. Median (interquartile range) intensive care unit length of stay, duration of mechanical ventilation, and number of day 28 ventilator-free days were 7.1 (3.6-11.3), 5.7 (2.6-10.3), and, 19.0 (0-24.2) days. Multiple logistic regression analysis identified underlying Charlson comorbidity score (odds ratio 3.11, 95% confidence interval 2.01-5.05) for each point increase, transfer admission from the floor or outside hospital (odds ratio 3.75, 95% confidence interval 1.41-10.99), day 3 cardiovascular failure (odds ratio 3.30, 95% confidence interval 1.19-9.92), and day 3 Pao2/Fio2 (odds ratio 0.94, 95% confidence interval 0.88-0.99) as significant predictors of 6-month mortality. CONCLUSIONS: With the implementation of recent advances in mechanical ventilation and supportive care, premorbid condition is the most important determinant of acute lung injury survival.

Integrin alpha9beta1 directly binds to vascular endothelial growth factor (VEGF)-A and contributes to VEGF-A-induced angiogenesis.

Vascular endothelial growth factor A (VEGF-A) is a potent inducer of angiogenesis. We now show that VEGF-A-induced adhesion and migration of human endothelial cells are dependent on the integrin alpha9beta1 and that VEGF-A is a direct ligand for this integrin. Adhesion and migration of these cells on the 165 and 121 isoforms of VEGF-A depend on cooperative input from alpha9beta1 and the cognate receptor for VEGF-A, VEGF receptor 2 (VEGF-R2). Unlike alpha3beta1or alphavbeta3 integrins, alpha9beta1 was also found to bind the 121 isoform of VEGF-A. This interaction appears to be biologically significant, because alpha9beta1-blocking antibody dramatically and specifically inhibited angiogenesis induced by VEGF-A165 or -121. Together with our previous findings that alpha9beta1 directly binds to VEGF-C and -D and contributes to lymphangiogenesis, these results identify the integrin alpha9beta1 as a potential pharmacotherapeutic target for inhibition of pathogenic angiogenesis and lymphangiogenesis.