- Internal Medicine
Clinical Associate Professor, Medicine
Clinical Associate Professor of Medicine, Stanford University School of Medicine, Hospitalist (2016 - Present)
Section Chief, General Medicine Service, Division of Hospital Medicine (2016 - Present)
B1/C1 Unit Based Medical Director, Stanford Hospital and Clinics (2012 - Present)
Faculty Member, E4C (Educators for Care) (2012 - Present)
Faculty Lead, School of Medicine Practice of Medicine Practicum Course (2009 - Present)
Core Faculty, Stanford Program in Bedside Medicine (Stanford 25) (2011 - Present)
Faculty Lead, School of Medicine Practice of Medicine Electronic Medical Records Curriculum (2011 - Present)
Committee Member, Stanford Hospital Health Information Management (HIM) Committee (2010 - Present)
Associate Director, Section of Hospital Medicine (2014 - 2016)
Clinical Assitant Professor of Medicine, Hospitalist, Stanford University School of Medicine (2010 - 2016)
Committee Member, Stanford Hospital Quality Council (2009 - 2015)
Committee Member, Department of Medicine Professional Practice Evaluation Committee (PPEC) (2011 - 2014)
Faculty Member, E4C (Educators For Care) Associates Program (2010 - 2012)
Committee Member, Stanford Hospital Pharmacy and Therapeutics Committee (2009 - 2012)
Committee Member, Stanford Hospital Paging/Communication Committee (2009 - 2011)
Coordinator, Stanford Hospital Nocturnist Program (2009 - 2010)
Clinical Instructor, Hospitalist, Stanford University School of Medicine (2008 - 2010)
Honors & Awards
G.D. Hsuing Research Fellowship, Yale Medical School (May 2001 - August 2001)
Medical Research Fellow, Howard Hughes Medical Institute (2003)
Annual Conference Travel Award, American Society of Hematology (2003)
Franklin G. Ebaugh, Jr. Research Award, Stanford Hospital Department of Medicine (2006, 2008)
Department of General Internal Medicine 2009 Teaching Award, Stanford Dept General Internal Medicine (2009)
"Excellence in Teaching" Pin, Stanford School of Medicine (2009, 2010)
Semi-Finalist - Poster Presentation, Society of Hospitalist Medicine Annual National Meeting (May 2011)
Faculty Fellow, Rathmann Family Foundation E4C Fellowship in Patient-centered Care (2011)
Award Recipient, Henry J Kaiser Family Foundation Award for Excellence in Preclinical Teaching (May 2012)
Boards, Advisory Committees, Professional Organizations
Regional Officer - Secretary/Treasurer, Society of General Internal Medicine (2013 - 2017)
Medical Education: Yale School Of Medicine (2005) CT
Residency: Stanford University Internal Medicine Residency (2008) CA
Board Certification: American Board of Internal Medicine, Internal Medicine (2008)
BA, Yale University, Biology (2000)
- MD Capstone Experience: Preparation for Residency
MED 397A (Spr)
- Independent Studies (5)
- Prior Year Courses
Ana Carolina Boncompagni, Arthur Brant, Meilin Dong, Michelle Drews, Gina Duronio, Melissa Eidman, Joshua Guild, Michelle Han, Tanvi Jayaraman, Tiffani Johnson, Arielle Kempinsky, Brandon Lam, Richard Liang, David Lu, Swapnil Mehta, Judith Mizrachi, Adi Mukund, Kamal Obbad, Ben Ober-Reynolds, Joshua Pickering, Claire Rhee, Bronwyn Scott, Jonathan Shi, Ashley Stevenson, Jesse Tai, Gavin Touponse, Elaine Tran, Emily Tran, Christian Ugaz Valencia, Timothy Wu, Anna Zeidman, Angela Zhang
- A Mixed Methods Approach to Understanding Curricular Impact of a Capstone Course on the Self-Efficacy of Fourth-Year Medical Students CUREUS 2020; 12 (8)
A Mixed Methods Approach to Understanding Curricular Impact of a Capstone Course on the Self-Efficacy of Fourth-Year Medical Students.
2020; 12 (8): e9537
Background Capstone, or bootcamp, courses have been shown to increase the knowledge, skills, and self-efficacy of students prior to starting intern year and have been recommended by the Alliance for Clinical Education (ACE) to be incorporated into the fourth-year medical school curricula. However, a paucity of research exists regarding the exploration of the student perspective on critical curricular content and teaching strategies in a capstone course. Self-efficacy, one's subjective task-specific judgment of capability, has served in the literature as a framework for capstone outcomes and is derived from four sources of experiences: practice, observation of others, feedback, and one's emotional reaction to difficult situations. Utilizing this framework, we aimed to evaluate the impact of our capstone curriculum on students' self-efficacy and to identify critical curricular content and teaching strategies that affected students' self-efficacy and their transition into residency. Methods We designed a mixed methods study of our institution's capstone course in May 2019. Students were invited to participate in the retrospective pre- and post- self-efficacy survey and focus group immediately after the capstone and in semi-structured interviews four months after they began the intern year. Themes were identified via qualitative analysis using inductive coding to allow participants' voices to guide code development and deductive analysis using codes derived from the self-efficacy framework. Results Nine enrolled students participated in the study (surveys n=8, focus group n=7, follow-up interview n=6). Students reported the capstone was a very valuable educational experience (median 4.5 [interquartile range, or IQR 4-5]), increased their preparedness for intern year (median 5 [IQR 4.25-5]) and increased self-efficacy in multiple domains. Qualitative analysis revealed the critical curricular elements that most impacted students' self-efficacy were practical and communication skills to which students previously had limited exposure, in particular managing acute clinical needs, overnight cross-cover pages, inpatient pharmacology, daily intern communication (handoffs, consults, consenting), and end-of-life communication (goals of care, code status, pronouncing death). While all four sources contributed to self-efficacy, students reported that instructor and peer feedback were fundamental to providing context and substance to their performance. Students preferred practice-based learning via high-fidelity simulation and small groups for familiar tasks (daily intern communication, overnight pages, pharmacology) and observation of peers for new tasks (end-of-life communication and acute clinical deterioration). Conclusions This is the first study describing students' perspectives on critical curricular content and teaching strategies for a capstone course derived from qualitative analysis. Practical and communication skills with previously limited clerkship exposure and task-specific learning strategies increased the students' self-efficacy. Constructive feedback provided an important source of self-efficacy for all tasks, augmenting the benefits of practice and observation. This data provides preliminary groundwork for future research as multi-institutional studies are necessary to better understand students' needs around the curriculum to address residency transition.
View details for DOI 10.7759/cureus.9537
View details for PubMedID 32905172
View details for PubMedCentralID PMC7465827
- CMS Billing Guidelines and Student Documentation: a New Era or New Burden? JOURNAL OF GENERAL INTERNAL MEDICINE 2019; 34 (4): 634–35
- Characterizing electronic health record usage patterns of inpatient medicine residents using event log data PLOS ONE 2019; 14 (2)
Characterizing electronic health record usage patterns of inpatient medicine residents using event log data.
2019; 14 (2): e0205379
Amid growing rates of burnout, physicians report increasing electronic health record (EHR) usage alongside decreasing clinical facetime with patients. There exists a pressing need to improve physician-computer-patient interactions by streamlining EHR workflow. To identify interventions to improve EHR design and usage, we systematically characterize EHR activity among internal medicine residents at a tertiary academic hospital across various inpatient rotations and roles from June 2013 to November 2016. Logged EHR timestamps were extracted from Stanford Hospital's EHR system (Epic) and cross-referenced against resident rotation schedules. We tracked the quantity of EHR logs across 24-hour cycles to reveal daily usage patterns. In addition, we decomposed daily EHR time into time spent on specific EHR actions (e.g. chart review, note entry and review, results review).In examining 24-hour usage cycles from general medicine day and night team rotations, we identified a prominent trend in which night team activity promptly ceased at the shift's end, while day team activity tended to linger post-shift. Across all rotations and roles, residents spent on average 5.38 hours (standard deviation = 2.07) using the EHR. PGY1 (post-graduate year one) interns and PGY2+ residents spent on average 2.4 and 4.1 times the number of EHR hours on information review (chart, note, and results review) as information entry (note and order entry).Analysis of EHR event log data can enable medical educators and programs to develop more targeted interventions to improve physician-computer-patient interactions, centered on specific EHR actions.
View details for PubMedID 30726208
How are medical students using the Electronic Health Record (EHR)?: An analysis of EHR use on an inpatient medicine rotation.
2019; 14 (8): e0221300
Physicians currently spend as much as half of their day in front of the computer. The Electronic Health Record (EHR) has been associated with declining bedside skills and physician burnout. Medical student EHR use has not been well studied or characterized. However, student responsibilities for EHR documentation will likely increase as the Centers for Medicare and Medicaid Services (CMS) most recent provisions now allow student notes for billing which will likely increase the role of medical student use of the EHR over time. To gain a better understanding of how medical students use the EHR at our institution, we retrospectively analyzed 6,692,994 EHR interactions from 49 third-year clerkship medical students and their supervising physicians assigned to the inpatient medicine ward rotation between June 25 2015 and June 24 2016 at a tertiary academic medical center. Medical students spent 4.42 hours (37%) of each day at the on the EHR and 35 minutes logging in from home. Improved understanding of student EHR-use and the effects on well-being warrants further attention, especially as EHR use increases with early trainees.
View details for DOI 10.1371/journal.pone.0221300
View details for PubMedID 31419265
- What's in a Name? Factors That Influence the Usage of Generic Versus Trade Names for Cardiac Medications Among Healthcare Providers CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES 2018; 11 (8)
- Acetaminophen or Tylenol? A Retrospective Analysis of Medication Digital Communication Practices JOURNAL OF GENERAL INTERNAL MEDICINE 2018; 33 (8): 1218–20
Duty-Hour Flexibility Trial in Internal Medicine
NEW ENGLAND JOURNAL OF MEDICINE
2018; 379 (3): 300
View details for Web of Science ID 000439063900020
- Lean-Based Redesign of Multidisciplinary Rounds on General Medicine Service JOURNAL OF HOSPITAL MEDICINE 2018; 13 (7): 482–85
Is it Time to Re-Examine the Physical Exam?
Journal of hospital medicine
2018; 13 (6): 433–34
View details for PubMedID 29858552
- Is it Time to Re-Examine the Physical Exam? JOURNAL OF HOSPITAL MEDICINE 2018; 13 (6): 433-434
Acetaminophen or Tylenol? A Retrospective Analysis of Medication Digital Communication Practices.
Journal of general internal medicine
View details for PubMedID 29717410
- MEDICATION COMMUNICATION PRACTICES BETWEEN PROVIDERS IN CARDIOLOGY ELSEVIER SCIENCE INC. 2018: 2644
The Role of Technology in the Bedside Encounter.
The Medical clinics of North America
2018; 102 (3): 443–51
Technology has the potential to both distract and reconnect providers with their patients. The widespread adoption of electronic medical records in recent years pulls physicians away from time at the bedside. However, when used in conjunction with patients, technology has the potential to bring patients and physicians together. The increasing use of point-of-care ultrasound by physicians is changing the bedside encounter by allowing for real-time diagnosis with the treating physician. It is a powerful example of the way technology can be a force for refocusing on the bedside encounter.
View details for PubMedID 29650066
What's in a Name? Factors That Influence the Usage of Generic Versus Trade Names for Cardiac Medications Among Healthcare Providers.
Circulation. Cardiovascular quality and outcomes
2018; 11 (8): e004704
View details for PubMedID 30354370
Lean-Based Redesign of Multidisciplinary Rounds on General Medicine Service.
Journal of hospital medicine
Multidisciplinary rounds (MDR) facilitate timely communication amongst the care team and with patients. We used Lean techniques to redesign MDR on the teaching general medicine service.To examine if our Lean-based new model of MDR was associated with change in the primary outcome of length of stay (LOS) and secondary outcomes of discharges before noon, documentation of estimated discharge date (EDD), and patient satisfaction.This is a pre-post study. The preperiod (in which the old model of MDR was followed) comprised 4000 patients discharged between September 1, 2013, and October 22, 2014. The postperiod (in which the new model of MDR was followed) comprised 2085 patients between October 23, 2014, and April 30, 2015.Lean-based redesign of MDR.LOS, discharges before noon, EDD, and patient satisfaction.There was no change in the mean LOS. Discharges before noon increased from 6.9% to 10.7% (P < .001). Recording of EDD increased from 31.4% to 41.3% (P < .001). There was no change in patient satisfaction.Lean-based redesign of MDR was associated with an increase in discharges before noon and in recording of EDD.
View details for PubMedID 29394300
A Pilot Study of the Chronology of Present Illness: Restructuring the HPI to Improve Physician Cognition and Communication.
Journal of general internal medicine
2017; 32 (2): 182-188
Patient history-taking is an essential clinical skill, with effects on diagnostic reasoning, patient-physician relationships, and more. We evaluated the impact of using a structured, timeline-based format, the Chronology of Present Illness (CPI), to guide the initial patient interaction.To determine the feasibility and impact of the CPI on the patient interview, written notes, and communication with other providers.Internal medicine residents used the CPI during a 2-week night-float rotation. For the first week, residents interviewed, documented, and presented patient histories according to their normal practices. They then attended a brief educational session describing the CPI, and were asked to use this method for new patient interviews, notes, and handoffs during the second week. Night and day teams evaluated the method using retrospective pre-post comparisons.Twenty-two internal medicine residents in their second or third postgraduate year.An educational dinner describing the format and potential benefits of using the CPI.Retrospective pre-post surveys on the efficiency, quality, and clarity of the patient interaction, written note, and verbal handoff, as well as open-ended comments. Respondents included night-float residents, day team residents, and attending physicians.All night-float residents responded, reporting significant improvements in written note, verbal sign-out, assessment and plan, patient interaction, and overall efficiency (p < 0.05). Day team residents (n = 76) also reported increased clarity in verbal sign-out and written note, improved efficiency, and improved preparedness for presenting the patient (p < 0.05). Attending physician ratings did not differ between groups.Resident ratings indicate that the CPI can improve key aspects of patient care, including the patient interview, note, and physician-physician communication. These results suggest that the method should be taught and implemented more frequently.
View details for DOI 10.1007/s11606-016-3928-3
View details for PubMedID 27896691
The Illness of Present Histories.
Academic medicine : journal of the Association of American Medical Colleges
2017; 92 (4): 434–35
View details for PubMedID 28350609
Can Secure Patient-Provider Messaging Improve Diabetes Care?
2017; 40 (10): 1342–48
Internet-based secure messaging between patients and providers through a patient portal is now common in the practice of modern medicine. There is limited evidence on how messaging is associated with use and clinical quality measures among patients with type 2 diabetes. We examine whether messaging with physicians for medical advice is associated with fewer face-to-face visits and better diabetes management.Patients with diabetes who were enrolled in an online portal of an outpatient health care organization in 2011-2014 were studied (N= 37,762 patient-years). Messages from/to primary care physicians or diabetes-related specialists for medical advice were considered. We estimated the association of messaging with diabetes quality measures, adjusting for patient and provider characteristics and patient-level clustering.Most patients (72%) used messaging, and those who made frequent visits were also more likely to message. Given visit frequency, no (vs. any) messaging was negatively associated with the likelihood of meeting an HbA1ctarget of <8% (64 mmol/mol) (odds ratio [OR] 0.83 [95% CI 0.77, 0.90]). Among message users, additional messages (vs. 1) were associated with better outcome (two more messages: OR 1.17 [95% CI 1.06, 1.28]; three more messages: 1.38 [1.25, 1.53]; four more messages: 1.55 [1.43, 1.69]). The relationship was stronger for noninsulin users. Message frequency was also positively associated, but to a smaller extent, with process measures (e.g., eye examination). Physician-initiated messages had effects similar to those for patient-initiated messages.Patients with diabetes frequently used secure messaging for medical advice in addition to routine visits to care providers. Messaging was positively associated with better diabetes management in a large community outpatient practice.
View details for PubMedID 28807977
Patient Outcomes when Housestaff Exceed 80 Hours per Week.
American journal of medicine
2016; 129 (9): 993-999 e1
It has been posited that high workload and long work hours for trainees could affect the quality and efficiency of patient care. Duty hour restrictions seek to balance patient care and resident education by limiting resident work hours. Through a retrospective cohort study, we investigate whether patient care on an inpatient general medicine service at a large academic medical center is impacted when housestaff work greater than eighty hours per week METHODS: We identified all admissions to a housestaff-run general medicine service between June 25, 2013 and June 29, 2014. Each hospitalization was classified by whether or not the patient was admitted by housestaff who have worked more than eighty hours a week during their hospitalization. Housestaff computer activity and duty hours were calculated by institutional electronic heath record audit, as well as length of stay and a composite of in-hospital mortality, ICU transfer rate, and 30-day readmission rate.We identified 4,767 hospitalizations by 3,450 unique patients; of which 40.9% of hospitalizations were managed by housestaff who worked more than eighty hours that week during their hospitalization. There was a significantly higher rate of the composite outcome (19.2% vs. 16.7%, p = 0.031) for patients admitted by housestaff working more than eighty hours a week during their hospitalization. We found a statistically significant higher length of stay (5.12 vs. 4.66 days, p = 0.048) and rate of ICU transfer (3.18% vs. 2.38%, p = 0.029). There was no statistically significant difference in 30-day readmission rate (13.7% vs. 12.8%, p = 0.395), or in-hospital mortality rate (3.18% vs. 2.42%, p = 0.115).There was no correlation with team census on admission and patient outcomes.Patients taken care of by housestaff working more than eighty hours a week had increased length of stay and number of ICU transfers. There was no association between resident work-hours and patient in-hospital mortality or 30-day readmission rate.
View details for DOI 10.1016/j.amjmed.2016.03.023
View details for PubMedID 27103047
The Five-Minute Moment.
American journal of medicine
2016; 129 (8): 792-795
In today's hospital and clinic environment, the obstacles to bedside teaching both for faculty and trainees are considerable. As Electronic Health Records (EHR) systems become increasingly prevalent, trainees are spending more time performing patient care tasks from computer workstations, limiting opportunities to learn at the bedside. Physical examination skills are rarely emphasized and low confidence levels, especially in junior faculty, pose additional barriers to teaching the bedside exam.
View details for DOI 10.1016/j.amjmed.2016.02.020
View details for PubMedID 26972793
Fulfilling outpatient medicine responsibilities during internal medicine residency: a quantitative study of housestaff participation with between visit tasks
BMC MEDICAL EDUCATION
Internal Medicine residents experience conflict between inpatient and outpatient medicine responsibilities. Outpatient "between visit" responsibilities such as reviewing lab and imaging data, responding to medication refill requests and replying to patient inquiries compete for time and attention with inpatient duties. By examining Electronic Health Record (EHR) audits, our study quantitatively describes this balance between competing responsibilities, focusing on housestaff participation with "between visit" outpatient responsibilities.We examined EHR log-in data from 2012-2013 for 41 residents (R1 to R3) assigned to a large academic center's continuity clinic. From the EHR log-in data, we examined housestaff compliance with "between visit" tasks, based on official clinic standards. We used generalized estimating equations to evaluate housestaff compliance with between visit tasks and amount of time spent on tasks. We examined the relationship between compliance with between visit tasks and resident year of training, rotation type (elective or required) and interest in primary care.Housestaff compliance with logging in to complete "between visit" tasks varied significantly depending on rotation, with overall compliance of 45 % during core inpatient rotations compared to 68 % during electives (p = 0.01). Compliance did not significantly vary by interest in primary care or training level. Once logged in, housestaff spent a mean 53 min per week logged in while on electives, compared to 55 min on required rotations (p = 0.90).Our study quantitatively highlights the difficulty of attending to outpatient responsibilities during busy core inpatient rotations, which comprise the bulk of residency at our institution and at others. Our results reinforce the need to continue development and study of innovative systems for coverage of "between visit" responsibilities, including shared coverage models among multiple residents and shared coverage models between residents and clinic attendings, both of which require a balance between clinic efficiency and resident ownership, autonomy and learning.
View details for DOI 10.1186/s12909-016-0665-6
View details for PubMedID 27160008
LOS OUTLIERS: A CHALLENGING PROBLEM FOR BOTH THE TEACHING AND PRIVATE NON-TEACHING GENERAL MEDICINE SERVICES AT STANFORD HOSPITAL
SPRINGER. 2016: S294
View details for Web of Science ID 000392201600372
- Internal Medicine Resident Computer Usage: An Electronic Audit of an Inpatient Service. JAMA internal medicine 2016; 176 (2): 252-254
Long-term outcomes of septal reduction for obstructive hypertrophic cardiomyopathy.
Journal of cardiology
2015; 66 (1): 57-62
Surgical myectomy and alcohol septal ablation (ASA) aim to decrease left ventricular outflow tract (LVOT) gradient in hypertrophic cardiomyopathy (HCM). Outcome of myectomy beyond 10 years has rarely been described. We describe 20 years of follow-up of surgical myectomy and 5 years of follow-up for ASA performed for obstructive HCM.We studied 171 patients who underwent myectomy for symptomatic LVOT obstruction between 1972 and 2006. In addition, we studied 52 patients who underwent ASA for the same indication and who declined surgery. Follow-up of New York Heart Association (NYHA) functional class, echocardiographic data, and vital status were obtained from patient records. Mortality rates were compared with expected mortality rates of age- and sex-matched populations.Surgical myectomy improved NYHA class (2.74±0.65 to 1.54±0.74, p<0.001), reduced resting gradient (67.4±43.4mmHg to 11.2±16.4mmHg, p<0.001), and inducible LVOT gradient (98.1±34.7mmHg to 33.6±34.9mmHg, p<0.001). Similarly, ASA improved functional class (2.99±0.35 to 1.5±0.74, p<0.001), resting gradient (67.1±26.9mmHg to 23.9±29.4mmHg, p<0.001) and provoked gradient (104.4±34.9mmHg to 35.5±38.6mmHg, p<0.001). Survival after myectomy at 5, 10, 15, and 20 years of follow-up was 92.9%, 81.1%, 68.9%, and 47.5%, respectively. Of note, long-term survival after myectomy was lower than for the general population [standardized mortality ratio (SMR)=1.40, p<0.005], but still compared favorably with historical data from non-operated HCM patients. Survival after ASA at 2 and 5 years was 97.8% and 94.7%, respectively. Short-term (5 year) survival after ASA (SMR=0.61, p=0.48) was comparable to that of the general population.Long-term follow-up of septal reduction strategies in obstructive HCM reveals that surgical myectomy and ASA are effective for symptom relief and LVOT gradient reduction and are associated with favorable survival. While overall prognosis for the community HCM population is similar to the general population, the need for surgical myectomy may identify a sub-group with poorer long-term prognosis. We await long-term outcomes of more extensive myectomy approaches adopted in the past 10 years at major institutions.
View details for DOI 10.1016/j.jjcc.2014.08.010
View details for PubMedID 25238885
- Clinical education and the electronic health record: the flipped patient. JAMA 2014; 312 (22): 2331-2332
- Medical students and the electronic health record: 'an epic use of time'. American journal of medicine 2014; 127 (9): 891-895
Assigning a team-based pager for on-call physicians reduces paging errors in a large academic hospital.
Joint Commission journal on quality and patient safety / Joint Commission Resources
2014; 40 (2): 77-82
As complexity of care of hospitalized patients has increased, the need for communication and collaboration among members of the team caring for the patient has become increasingly important. This often takes the form of a nurse's need to contact a patient's physician to discuss some aspect of care and modify treatment plans. Errors in communication delay care and can pose risk to patients. This report describes the successful implementation of a standardized team-based paging system at an academic center. Results showed a substantial improvement in nurses' perceptions of knowing how to contact the correct physician when discussion of the patient's care is needed. This improvement was found across multiple medical and surgical specialties and was particularly effective for services with the greatest communication problems.
View details for PubMedID 24716330
- Improving communication with patients: learning by doing. JAMA-the journal of the American Medical Association 2013; 310 (21): 2257-2258
- A piece of my mind. The road back to the bedside. JAMA-the journal of the American Medical Association 2013; 310 (8): 799-800
PAGING EFFECTIVENESS: A MODEL FOR PAGER COMMUNICATION AT A LARGE ACADEMIC MEDICAL CENTER
SPRINGER. 2011: S552
View details for Web of Science ID 000208812703224
A cascade of Ca2+/calmodulin-dependent protein kinases regulates the differentiation and functional activation of murine neutrophils
2008; 36 (7): 832-844
The function of neutrophils as primary mediators of innate immunity depends on the activity of granule proteins and critical components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Expression of their cognate genes is regulated during neutrophil differentiation by a complex network of intracellular signaling pathways. In this study, we have investigated the role of two members of the calcium/calmodulin-dependent protein kinase (CaMK) signaling cascade, CaMK I-like kinase (CKLiK) and CaMKKalpha, in regulating neutrophil differentiation and functional activation.Mouse myeloid cell lines were used to examine the expression of a CaMK cascade in developing neutrophils and to examine the effects of constitutive activation vs inhibition of CaMKs on neutrophil maturation.Expression of CaMKKalpha was shown to increase during neutrophil differentiation in multiple cell lines, whereas expression of CKLiK increased as multipotent progenitors committed to promyelocytes, but then decreased as cells differentiated into mature neutrophils. Expression of constitutively active CKLiKs did not affect morphologic maturation, but caused dramatic decreases in both respiratory burst responses and chemotaxis. This loss of neutrophil function was accompanied by reduced secondary granule and gp91(phox) gene expression. The CaMK inhibitor KN-93 attenuated cytokine-stimulated proliferative responses in promyelocytic cell lines, and inhibited the respiratory burst. Similar data were observed with the CaMKKalpha inhibitor, STO-609.Overactivation of a cascade of CaMKs inhibits neutrophil maturation, suggesting that these kinases play an antagonistic role during neutrophil differentiation, but at least one CaMK is required for myeloid cell expansion and functional activation.
View details for DOI 10.1016/j.exphem.2008.02.009
View details for Web of Science ID 000257349400010
View details for PubMedID 18400360
Heterogeneity of functional responses in differentiated myeloid cell lines reveals EPRO cells as a valid model of murine neutrophil functional activation
JOURNAL OF LEUKOCYTE BIOLOGY
2005; 77 (5): 669-679
Mature neutrophils display multiple functional responses upon activation that include chemotaxis, adhesion to and transmigration across endothelial cells, phagocytosis, and pathogen destruction via potent microbicidal enzymes and reactive oxygen species. We are using myeloid cell line models to investigate the signaling pathways that govern neutrophil functional activation. To facilitate these studies, we have performed a direct comparison of functional responses of human and murine myeloid cell line models upon neutrophil differentiation. Our results show that EPRO cells, promyelocytes that undergo complete neutrophil maturation, demonstrate a full spectrum of functional responses, including respiratory burst, chemotaxis toward two murine chemokines, and phagocytosis. We also extend previous studies of granulocyte-colony stimulating factor-induced 32Dcl3 cells, showing they demonstrate chemotaxis and phogocytosis but completely lack a respiratory burst as a result of the absent expression of a critical oxidase subunit, gp91(phox). Induced human leukemic NB4 and HL-60 cells display a respiratory burst and phagocytosis but have defective chemotaxis to multiple chemoattractants. We also tested each cell line for the ability to up-regulate cell-surface membrane-activated complex-1 (Mac-1) expression upon activation, a response mediating neutrophil adhesion and a surrogate marker for degranulation. We show that EPRO cells, but not 32Dcl3 or NB4, significantly increase Mac-1 surface expression upon functional activation. Together, these data show that EPRO and MPRO cells demonstrate complete, functional activation upon neutrophil differentiation, suggesting these promyelocytic models accurately reflect the functional capacity of mature murine neutrophils.
View details for DOI 10.1189/jlb.1004567
View details for Web of Science ID 000228875500008
View details for PubMedID 15673544