Outcome and Prognostic Indicators of Patients with Hematopoietic Stem Cell Transplants Admitted to the Intensive Care Unit

The prognosis of patients with hematopoietic stem cell transplants (HSCTs) who require admission to the intensive care unit (ICU) has been regarded as extremely poor. We sought to re-evaluate recent outcomes and predictive factors in a retrospective cohort study. Among the 605 adult patients that received an HSCT between 2001 and 2006, 154 required admission to the ICU. Of these, 47% were discharged from the ICU, 36% were discharged from the hospital, and 19% survived 6 months. Allogeneic transplant, mechanical ventilation, vasopressor-use, and neutropenia were each associated with increased mortality, and the mortality of patients with all four characteristics was 100%. Hemodialysis was also associated with increased mortality in a Kaplan-Meier analysis but did not appear important in a multivariate tree analysis. A final Cox model confirmed that allogeneic transplant, mechanical ventilation, and vasopressor-use were each independent risk factors for mortality in the 6 months following ICU admission

CXCR2 is critical for dsRNA-induced lung injury: relevance to viral lung infection

BACKGROUND: Respiratory viral infections are characterized by the infiltration of leukocytes, including activated neutrophils into the lung that can lead to sustained lung injury and potentially contribute to chronic lung disease. Specific mechanisms recruiting neutrophils to the lung during virus-induced lung inflammation and injury have not been fully elucidated. Since CXCL1 and CXCL2/3, acting through CXCR2, are potent neutrophil chemoattractants, we investigated their role in dsRNA-induced lung injury, where dsRNA (Poly IC) is a well-described synthetic agent mimicking acute viral infection. METHODS: We used 6–8 week old female BALB/c mice to intratracheally inject either single-stranded (ssRNA) or double-stranded RNA (dsRNA) into the airways. The lungs were then harvested at designated timepoints to characterize the elicited chemokine response and resultant lung injury following dsRNA exposure as demonstrated qualititatively by histopathologic analysis, and quantitatively by FACS, protein, and mRNA analysis of BAL fluid and tissue samples. We then repeated the experiments by first pretreating mice with an anti-PMN or corresponding control antibody, and then subsequently pretreating a separate cohort of mice with an anti-CXCR2 or corresponding control antibody prior to dsRNA exposure. RESULTS: Intratracheal dsRNA led to significant increases in neutrophil infiltration and lung injury in BALB/c mice at 72 h following dsRNA, but not in response to ssRNA (Poly C; control) treatment. Expression of CXCR2 ligands and CXCR2 paralleled neutrophil recruitment to the lung. Neutrophil depletion studies significantly reduced neutrophil infiltration and lung injury in response to dsRNA when mice were pretreated with an anti-PMN monoclonal Ab. Furthermore, inhibition of CXCR2 ligands/CXCR2 interaction by pretreating dsRNA-exposed mice with an anti-CXCR2 neutralizing Ab also significantly attenuated neutrophil sequestration and lung injury. CONCLUSION: These findings demonstrate that CXC chemokine ligand/CXCR2 biological axis is critical during the pathogenesis of dsRNA-induced lung injury relevant to acute viral infections

Last interglacial (MIS 5e) sea-level determined from a tectonically stable, far-field location, Eyre Peninsula, southern Australia

The last interglacial maximum (Marine Isotope Substage 5e [MIS 5e], 128¿116 ka) is a distinctive event in recent Earth history. Shoreline successions of this age are important for calibrating climate models and defining the overall behaviour of the crust¿mantle system to fluctuating ice and ocean-water volumes. In a global context, the recently intensified interest in last interglacial shoreline successions has revealed considerable variability in the magnitude of sea-level rise during this time interval and highlighted the need to examine paleosea-level evidence from tectonically stable, far-field settings. Situated in the far-field of continental ice sheets and on the tectonically stable Gawler Craton, the 300 km coastal sector of western Eyre Peninsula between Fowlers Bay and Lake Newland in southern Australia represents an important region for defining the glacio-eustatic (ice-equivalent) sea-level attained during the last interglacial maximum based on the relative sea-level observations from this region. Low-energy, shoaling upward, peritidal bioclastic carbonate successions of the last interglacial (locally termed Glanville Formation) formed within back-barrier, estuarine¿lagoonal environments in the lee of eolianite barrier complexes (locally termed Bridgewater Formation) along this coastline. The well-preserved shelly successions (coquinas) contain diverse molluscan fossil assemblages including species no longer living in the coastal waters of South Australia (e.g. the Sydney cockle Anadara trapezia and the benthic foraminifer Marginopora vertebralis). The extent of amino acid racemisation (a measure of fossil age based on increasing d/l value) in a range of species, and in particular A. trapezia and Katelysia sp., confirms the time equivalence of the isolated embayment-fill successions, correlated with the informal type section of the Glanville Formation at Dry Creek, north of Adelaide. Preliminary U-series analyses on A. trapezia also suggest a correlation with the last interglacial maximum, but further highlight the complexity in dating fossil molluscs by the U-series method in view of their open-system behaviour. The shelly successions of the Glanville Formation occur at elevations higher than attained by sea-level in the current, Holocene interglacial. A higher sea-level of between 2.1 ± 0.5 and 4 ± 0.5 m above present sea-level is inferred for the last interglacial maximum (MIS 5e) along this coastline based on the elevation of sedimentary successions host to the shallow subtidal¿intertidal fossil molluscs Katelysia sp., and Anadara trapezia. The paleosea-level observations place a lower limit on the sea-level attained during the last interglacial maximum and suggest that caution be exercised in the definition of the upper limit of sea-level during this interglacial

CXC chemokines in angiogenesis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141036/1/jlb0001.pd

Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction.

BackgroundChronic Lung Allograft Dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Although CLAD is usually not responsive to treatment, earlier identification may improve treatment prospects.MethodsIn a nested case control study, 1-year post transplant surveillance bronchoalveolar lavage (BAL) fluid samples were obtained from incipient CLAD (n = 9) and CLAD free (n = 8) lung transplant recipients. Incipient CLAD cases were diagnosed with CLAD within 2 years, while controls were free from CLAD for at least 4 years following bronchoscopy. Transcription profiles in the BAL cell pellets were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression analysis, based on an absolute fold change (incipient CLAD vs no CLAD) >2.0 and an unadjusted p-value ≤0.05, generated a candidate list containing 55 differentially expressed probe sets (51 up-regulated, 4 down-regulated).ResultsThe cell pellets in incipient CLAD cases were skewed toward immune response pathways, dominated by genes related to recruitment, retention, activation and proliferation of cytotoxic lymphocytes (CD8+ T-cells and natural killer cells). Both hierarchical clustering and a supervised machine learning tool were able to correctly categorize most samples (82.3% and 94.1% respectively) into incipient CLAD and CLAD-free categories.ConclusionsThese findings suggest that a pathobiology, similar to AR, precedes a clinical diagnosis of CLAD. A larger prospective investigation of the BAL cell pellet transcriptome as a biomarker for CLAD risk stratification is warranted

Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine

<p>Abstract</p> <p>Background</p> <p>While lung transplantation is an increasingly utilized therapy for advanced lung diseases, chronic rejection in the form of Bronchiolitis Obliterans Syndrome (BOS) continues to result in significant allograft dysfunction and patient mortality. Despite correlation of clinical events with eventual development of BOS, the causative pathophysiology remains unknown. Airway epithelial cells within the region of inflammation and fibrosis associated with BOS may have a participatory role.</p> <p>Methods</p> <p>Transplant derived airway epithelial cells differentiated in air liquid interface culture were treated with IL-1β and/or cyclosporine, after which secretion of cytokines and growth factor and gene expression for markers of epithelial to mesenchymal transition were analyzed.</p> <p>Results</p> <p>Secretion of IL-6, IL-8, and TNF-α, but not TGF-β1, was increased by IL-1β stimulation. In contrast to previous studies using epithelial cells grown in submersion culture, treatment of differentiated cells in ALI culture with cyclosporine did not elicit cytokine or growth factor secretion, and did not alter IL-6, IL-8, or TNF-α production in response to IL-1β treatment. Neither IL-1β nor cyclosporine elicited expression of markers of the epithelial to mesenchymal transition E-cadherin, EDN-fibronectin, and α-smooth muscle actin.</p> <p>Conclusion</p> <p>Transplant derived differentiated airway epithelial cell IL-6, IL-8, and TNF-α secretion is not regulated by cyclosporine <it>in vitro</it>; these cells thus may participate in local inflammatory responses in the setting of immunosuppression. Further, treatment with IL-1β did not elicit gene expression of markers of epithelial to mesenchymal transition. These data present a model of differentiated airway epithelial cells that may be useful in understanding epithelial participation in airway inflammation and allograft rejection in lung transplantation.</p

Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis

Abstract Background Pulmonary sarcoidosis involves an intense leukocyte infiltration of the lung with the formation of non-necrotizing granulomas. CC chemokines (chemokine (C-C motif) ligand 2 (CCL2)-CCL5) are chemoattractants of mononuclear cells and act through seven transmembrane G-coupled receptors. Previous studies have demonstrated conflicting results with regard to the associations of these chemokines with sarcoidosis. In an effort to clarify previous discrepancies, we performed the largest observational study to date of CC chemokines in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis. Results BALF chemokine levels from 72 patients affected by pulmonary sarcoidosis were analyzed by enzyme-linked immunosorbent assay (ELISA) and compared to 8 healthy volunteers. BALF CCL3 and CCL4 levels from pulmonary sarcoidosis patients were not increased compared to controls. However, CCL2 and CCL5 levels were elevated, and subgroup analysis showed higher levels of both chemokines in all stages of pulmonary sarcoidosis. CCL2, CCL5, CC chemokine receptor type 1 (CCR1), CCR2 and CCR3 were expressed from mononuclear cells forming the lung granulomas, while CCR5 was only found on mast cells. Conclusions These data suggest that CCL2 and CCL5 are important mediators in recruiting CCR1, CCR2, and CCR3 expressing mononuclear cells as well as CCR5-expressing mast cells during all stages of pulmonary sarcoidosis

An Unorthodox Introduction to QCD

These are lecture notes presented at the 2017 CTEQ Summer School at the University of Pittsburgh and the 2018 CTEQ Summer School at the University of Puerto Rico, Mayaguez. The title is a reference to hep-th/0309149 and introduces perturbative QCD and its application to jet substructure from a bottom-up perspective based on the approximation of QCD as a weakly-coupled, conformal field theory. Using this approach, a simple derivation of the Sudakov form factor with soft gluon emission modeled as a Poisson process is presented. Topics of the identification and discrimination of quark- versus gluon-initiated jets and jet grooming are also discussed.Comment: 16 pages, 18 figures. Comments welcome!, v2: updated to include both lectures from the 2018 CTEQ schoo

The Stromal Derived Factor–1/CXCL12–CXC Chemokine Receptor 4 Biological Axis in Non–Small Cell Lung Cancer Metastases

Non-small cell lung cancer is characterized by a specific metastatic pattern. The mechanism for organ-specific metastasis is poorly understood, although evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis. We hypothesized that the CXCL12-CXCR4 biological axis is important in mediating non-small cell lung cancer metastases. Our results indicate that both non-small cell lung cancer tumor specimens resected from patients and non-small cell lung cancer cell lines express CXCR4, but not CXCL12. Non-small cell lung cancer cell lines undergo chemotaxis in response to CXCL12.CXCL12-CXCR4 activation of non-small cell lung cancer cell lines showed intracellular calcium mobilization and mitogen-activated protein kinase activation with enhanced extracellular signal-related kinase-1/2 phosphorylation without change in either proliferation or apoptosis. Target organs in a murine model that are the preferred destination of human non-small cell lung cancer metastases elaborate higher levels of CXCL12 than does the primary tumor; and suggest the generation of chemotactic gradients. The administration of specific neutralizing anti-CXCL12 antibodies to severe combined immunodeficient mice expressing human non-small cell lung cancer abrogated organ metastases, without affecting primary tumor-derived angiogenesis. These data suggest that the CXCL12-CXCR4 biological axis is involved in regulating the metastasis of non-small cell lung cancer

Facies and faunal assemblage changes in response to the Holocene transgression in the Lagoon of Mayotte (Comoro Archipelago, SW Indian Ocean)

This paper documents the facies change in response to the Holocene transgression within five sediment cores taken in the lagoon of Mayotte, which contain a Type-1 depositional sequence (lowstand, transgressive and highstand deposits underlain by an erosive sequence boundary). Quantitative compositional analysis and visual examination of the bioclasts were used to document the facies changes. The distribution of the skeletal and non-skeletal grains in the lagoon of Mayotte is clearly controlled by (1) the rate and amplitude of the Holocene sea-level rise, (2) the pre-Holocene basement topography and (3) the growth-potential of the barrier reef during sea-level rise, and the changes in bathymetry and continuity during this period. The sequence boundary consists of the glacial karst surface. The change-over from the glacial lowstand is marked by the occurrence of mangrove deposits. Terrigenous and/or mixed terrigenous-carbonate muds to sandy muds with a mollusc or mollusc-ostracod assemblage dominate the transgressive deposits. Mixed carbonate-siliciclastic or carbonate sand to gravel with a mollusc-foraminifer or mollusc-coral-foraminifer assemblage characterize the early highstand deposits on the inner lagoonal plains. The early highstand deposits in the outer lagoonal plains consist of carbonate muds with a mollusc-foraminifer assemblage. Late highstand deposits consist of terrigenous muds in the nearshore bays, mixed terrigenous-carbonate sandy muds to sands with a mollusc-foraminifer assemblage on the inner lagoonal plains and mixed muds with a mollusc-foraminifer assemblage on the outer deep lagoonal plains. The present development stage of the individual lagoons comprises semi-enclosed to open lagoons with fair or good water exchange with the open ocean