School of Medicine Faculty Papers

Permanent URI for this collectionhttps://digital.lib.washington.edu/handle/1773/15657

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Inflammation contributes to trauma-induced coagulopathy by oxidation of multiple clotting factors.
(2025-12-01) Han, Chang Yeop; St. John, Alexander E.; Kim, Jung Heon; Wang, Xu; Ringgold, Kristyn M.; Neidig, Lauren E.; Berenson, Ronald; Stern, Susan A.; White, Nathan J.
Trauma-induced coagulopathy (TIC) induces anticoagulation and increases bleeding mortality. Inflammation and oxidative stress play an unknown role in TIC. We examined plasma from injured human trauma patients presenting to the Emergency Department compared to healthy controls to elucidate the contribution of inflammation and oxidative stress to anticoagulation during TIC. Trauma patients demonstrated coagulopathy by prolongation of clotting time assays and decreased thrombin generation in addition to increased pro-inflammatory cytokines and increased markers of oxidative stress. Clotting factors seven (FVII), ten (FX), and twelve (FXII) were oxidatively modified without quantitative changes, displaying decreased activity after trauma. Factor five (FV) was decreased in concentration and retained normal activity. Factor eight (FVIII) concentration and activity were increased after trauma. Clotting factor oxidation after exposure to activated human leukocytes in vitro also impaired thrombin generation and reproduced the oxidative and functional changes seen in trauma patients. Both antioxidant and anti-inflammatory treatments prevented clotting factor oxidation and TIC after trauma in vivo using a rodent TIC model. These results suggest that inflammation and oxidative stress contribute directly to anticoagulation during TIC by direct and selective oxidation of clotting factors. FXII may make a novel contribution to the pathophysiology of TIC by its oxidation.
CARING FOR WASHINGTON’S OLDER ADULTS IN THE COVID-19 PANDEMIC: INTERVIEWS WITH ORGANIZATION LEADERS ABOUT THE STATE OF SOCIAL AND HEALTHCARE SERVICES
(2020-10-09) Berridge, Clara; Parsey, Carolyn M; Ramirez, Maggie; Freitag, Callie; Johnson, Ian; Allard, Scott W
The COVID-19 pandemic presents significant and costly disruptions to social service and health care systems. Eight in ten deaths from the COVID-19 virus in the U.S. have occurred in people age 65 and older (CDC, 2020). In addition to the mortality risk, the pandemic presents grave health and economic risks by disrupting services to older adults that prevent institutionalization, emergency room visits, and other negative health outcomes. This report examines how the pandemic has affected the operation of social service and healthcare organizations that support Washington’s 1.7 million older adults (60+), including 107,000 people with Alzheimer’s disease and other dementias. Drawing on surveys and interviews with 45 senior leaders of social services and health care organizations serving older adults throughout Washington State, this report identifies current challenges confronting service delivery and client care, as well as those that will persist to shape future strategy and planning. Several key findings and themes emerge relevant to policy and practice.
Potential of essential fatty acid deficiency with extremely low fat diet in lipoprotein lipase deficiency during pregnancy: A case report
(2004) Tsai, Elaine C.; Brown, Judy A.; Veldee, Megan Y.; Anderson, Gregory J.; Chait, Alan; Brunzell, John D.
Background: Pregnancy in patients with lipoprotein lipase deficiency is associated with high risk of maternal pancreatitis and fetal death. A very low fat diet (less than 10% of calories) is the primary treatment modality for the prevention of acute pancreatitis, a rare but potentially serious complication of severe hypertriglyceridemia. Since pregnancy can exacerbate hypertriglyceridemia in the genetic absence of lipoprotein lipase, a further reduction of dietary fat intake to less than 1-2% of total caloric intake may be required during the pregnancy, along with the administration of a fibrate. It is uncertain if essential fatty acid deficiency will develop in the mother and fetus with this extremely low fat diet, or whether fibrates will cross the placenta and concentrate in the fetus. Case presentation: A 23 year-old gravida 1 woman with primary lipoprotein lipase deficiency was seen at 7 weeks of gestation in the Lipid Clinic for management of severe hypertriglyceridemia that had worsened with pregnancy. While on her habitual fat intake of 10% of total calories, her pregnancy resulted in an exacerbation of the hypertriglyceridemia, which prompted further restriction of fat intake to less than 2% of total calories, as well as administration of gemfibrozil at a lower than average dose. The level of gemfibrozil, as the active metabolite, in the venous and arterial fetal cord blood was within the expected therapeutic range for adults. The clinical signs and a biomarker of essential fatty acid deficiency, namely the ratio of 20:3 [n-9] to 20:4 [n-6] fatty acids, were closely monitored throughout her pregnancy. Despite her extremely low fat diet, the levels of essential fatty acids measured in the mother and in the fetal blood immediately postpartum were normal. Normal essential fatty acid levels may have been achieved by the topical application of sunflower oil. Conclusions: An extremely low fat diet in combination with topical sunflower oil and gemfibrozil administration was safely implemented in pregnancy associated with the severe hypertriglyceridemia of lipoprotein lipase deficiency.
Bacterial neuraminidase facilitates mucosal infection by participating in biofilm production
(2006-08-01) Soong, Grace; Muir, Amanda; Gomez, Marisa I.; Waks, Jonathan; Reddy, Bharat; Planet, Paul; Singh, Pradeep; Kanetko, Yukihiro; Wolfgang, Matthew C.; Hsiao, Yu-Shan; Tong, Liang; Prince, Alice
Many respiratory pathogens, including Hemophilus influenzae, Streptococcus pneumoniae, and Pseudomonas aeruginosa, express neuraminidases that can cleave α2,3-linked sialic acids from glycoconjugates. As mucosal surfaces are heavily sialylated, neuraminidases have been thought to modify epithelial cells by exposing potential bacterial receptors. However, in contrast to neuraminidase produced by the influenza virus, a role for bacterial neuraminidase in pathogenesis has not yet been clearly established. We constructed a mutant of P. aeruginosa PAO1 by deleting the PA2794 neuraminidase locus (Δ2794) and tested its virulence and immunostimulatory capabilities in a mouse model of infection. Although fully virulent when introduced i.p., the Δ2794 mutant was unable to establish respiratory infection by i.n. inoculation. The inability to colonize the respiratory tract correlated with diminished production of biofilm, as assessed by scanning electron microscopy and in vitro assays. The importance of neuraminidase in biofilm production was further demonstrated by showing that viral neuraminidase inhibitors in clinical use blocked P. aeruginosa biofilm production in vitro as well. The P. aeruginosa neuraminidase has a key role in the initial stages of pulmonary infection by targeting bacterial glycoconjugates and contributing to the formation of biofilm. Inhibiting bacterial neuraminidases could provide a novel mechanism to prevent bacterial pneumonia.
Integrative analysis of RUNX1 downstream pathways and target genes
(2008) Michaud, Joelle; Simpson, Ken M.; Escher, Robert; Buchet-Poyau, Karine; Beissbarth, Tim; Carmichael, Catherine; Ritchie, Matthew E.; Schutz, Frederic; Cannon, Ping; Liu, Marjorie; Shen, Xiaofeng; Ito, Yoshiaki; Raskind, Wendy H.; Horwitz, Marshall S.; Osato, Motomi; Turner, David R.; Speed, Terence P.; Kavallaris, Maria; Smyth, Gordon K.; Scott, Hamish S.
Background: The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Results: Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBF[Beta], and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBF[Beta]. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. Conclusion: This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both familial and sporadic leukemia as well as therapeutic implications.
Enzyme estimates of infarct size correlate with functional and clinical outcomes in the setting of ST-segment elevation myocardial infarction
(2005-08-23) Every, Nathan R.
Background: Cardiac biomarkers are routinely obtained in the setting of suspected myocardial ischemia and infarction. Evidence suggests these markers may correlate with functional and clinical outcomes, but the strength of this correlation is unclear. The relationship between enzyme measures of myocardial necrosis and left ventricular performance and adverse clinical outcomes were explored. Methods: Creatine kinase (CK) and CK-MB data were analyzed, as were left ventricular ejection fraction (LVEF) by angiogram, and infarct size by single-photon emission computed tomography (SPECT) imaging in patients in 2 trials: Prompt Reperfusion In Myocardial-infarction Evolution (PRIME), and Efegatran and Streptokinase to Canalize Arteries Like Accelerated Tissue plasminogen activator (ESCALAT). Both trials evaluated efegatran combined with thrombolysis for treating acute ST-segment elevation myocardial infarction (STEMI). Results: Peak CK and CK area-under-the-curve (AUC) correlated significantly with SPECTdetermined infarct size 5 to 10 days after enrollment. Peak CK had a statistically significant correlation with LVEF, but CK-AUC and LVEF correlation were less robust. Statistically significant correlations exist between SPECT-determined infarct size and peak CK-MB and CK-MB AUC. However, there was no correlation with LVEF for peak CK-MB and CK-MB AUC. The combined outcome of congestive heart failure and death were significantly associated with CK AUC, CK-MB AUC, peak CK, and peak CK-MB measurements. Conclusion: Peak CK and CK-MB values and AUC calculations have significant correlation with functional outcomes (LVEF- and SPECT-determined infarct size) and death or CHF outcomes in the setting of STEMI. Cardiac biomarkers provide prognostic information and may serve as valid endpoint measurements for phase II clinical trials.

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