Larry Chu, MD is a Professor of Anesthesiology, Perioperative and Pain Medicine and Director of the Stanford Anesthesia Informatics and Media (AIM) Lab. Dr. Chu founded the START online educational program as well as the Learnly online learning ecosystem for post-graduate anesthesiology education. He is an NIH-funded clinical researcher and is Executive Director of Stanford Medicine X, the world's most-discussed academic program on emerging technology and medicine. He also directs Medicine X | ED, a conference exploring the future of patient-centered medical education. He has written eight books, over 50 papers and over 50 book chapters in academic anesthesiology. He is a member of the editorial advisory board for The BMJ, one of the most influential general medical journals in the world.
- Emerging Technology and Medicine
- Precision Medicine
- Digital Health Efficacy and Validation
- Patient Partnership in Academic Medicine
Editorial Advisory Board, The BMJ (2016 - 2018)
Executive Director, Stanford Medicine X (2011 - Present)
Member, Committee on Admissions, Stanford University School of Medicine (2007 - Present)
Electronic Media and Information Technology Committee, American Society of Anesthesiologists (2002 - 2004)
Trustee, California Medical Association (2003 - 2004)
Member, Editorial Board, MDNetGuide (1999 - Present)
Member, Educational Resources Committee, Society for Education in Anesthesia (2003 - Present)
Member, Web Site Committee, American Pain Society (2007 - Present)
Organizing Chair, Fourth World Congress on Social Media and Web 2.0 in Health, Medicine and Biomedical Research (2010 - 2011)
Honors & Awards
Excellence in Teaching Award, Stanford University Department of Biological Sciences (1998)
Research Fellowship Grant, Foundation for Anesthesia Education and Research (1/2003-6/2004)
Clinical Loan Repayment Program, National Institutes of Health (7/2003 - 7/2006)
Career Development Award, National Institutes of Health (8/2004-8/2009)
Innovation in Education Award, International Anesthesia Research Society (2011-2012)
Independent Scientist Award, National Institutes of Health (2013 - 2018)
Boards, Advisory Committees, Professional Organizations
Editorial Advisory Board Member, BMJ (2016 - Present)
Fellowship:Stanford University School of Medicine Registrar (2004) CA
Residency:Stanford University School of Medicine Registrar (2003) CA
Internship:St Marys Medical Center (2000) CA
Board Certification: Anesthesia, American Board of Anesthesiology (2004)
Medical Education:Stanford University School of Medicine (1999) CA
MS, Stanford University, Clinical Epidemiology (2006)
Fellowship, Stanford Medical School, Clinical Pain Research (2004)
Residency, Stanford Hospital, Anesthesiology (2003)
Internship, St. Mary's Hospital, Internal Medicine (2000)
MD, Stanford Medical School, Medicine (1999)
Current Research and Scholarly Interests
I have two lines of research, one involving educational informatics and use of technology in postgraduate medical education and another involving NIH-funded work in patient-oriented clinical research regarding opioid use and physiologic responses associated with acute and chronic exposure in humans.
For a full description of my educational informatics work, please see my website aim.stanford.edu.
My clinical research focuses on the study opiate-induced hyperalgesia in patients suffering from chronic pain.
I am currently conducting an NIH-funded five year double-blinded randomized controlled clinical study (NIGMS award 1K23GM071400-01) that prospectively examines the following hypotheses: 1) pain patients on chronic opioid therapy develop dose-dependent tolerance and/or hyperalgesia to these medications over time, 2) opiate-induced tolerance and hyperalgesia develop differently with respect to various types of pain, 3) opioid-induced hyperalgesia occurs independently of withdrawal phenomena, and 4) opiate-induced tolerance and hyperalgesia develop differently based on gender and/or ethnicity.
The study is the first quantitative and prospective examination of tolerance and hyperalgesia in pain patients and may have important implications for the rational use of opioids in the treatment of chronic pain.
Study on the Effect of a Beta Blocker on Increased Sensitivity to Pain in Humans Caused by Opioids
This research study explores whether a beta-blocker can prevent a person from becoming more sensitive to pain after administration of an opioid. Beta blockers inhibit the sympathetic (fight or flight) response and are often used to treat angina and high blood pressure. In a previous study in human volunteers, the investigators demonstrated an increased sensitivity to pain after a 60-minute infusion of the opioid remifentanil. The goal of this study is to identify a possible inhibitor of this phenomenon.
5HT3 Antagonists to Treat Opioid Withdrawal and to Prevent the Progression of Physical Dependence
Opioid medications are commonly used for pain relief. When given over time, physical dependence can occur. This results in unpleasant side effects--such as agitation and nausea--if opioid medications are suddenly stopped. This study aims to test the use of the drug ondansetron to reduce the symptoms associated with opioid withdrawal and to prevent the progression of opioid physical dependence, thereby allowing future investigators to better test the role of physical dependence in the development of addiction and also possibly improving acceptance of abstinence-based programs for addiction.
Stanford is currently not accepting patients for this trial. For more information, please contact Larry Chu, MD, MS, 650-724-2970.
A Study of Genetic Variation Influencing Pain and Response to Opioid Medications
The investigators will be collecting saliva DNA samples from chronic back pain patients. The investigators hope to find candidate genes associated with response to opioid medication by correlating molecular genetics data with pain measurement and opioid responsiveness data including opioid hyperalgesia and opioid analgesic tolerance.
Stanford is currently not accepting patients for this trial. For more information, please contact Dan Hoang, (650) 887 - 4677.
Functional Magnetic Resonance Imaging of Opioid Withdrawal in Healthy Human Volunteers
Opioid medications are commonly used for pain relief. When given over time, physical dependence can occur. This results in unpleasant side effects--such as agitation and nausea--if opioid medications are suddenly stopped. However, we do not know how withdrawal affects the brain. We know that a medication named Ondansetron can help ease or prevent symptoms associated with opioid withdrawal. Through imaging of the brain by fMRI, we hope to see how opioid withdrawal, with and without the administration of ondansetron, affects brain activity.
Stanford is currently not accepting patients for this trial. For more information, please contact Anna Clemenson, (650) 887 - 4677.
Opiate-Induced Tolerance & Hyperalgesia in Pain Patients
Opiates such as morphine are the cornerstone medications for the treatment of moderate to severe pain. Recent evidence suggests that pain patients on chronic opioid therapy become more sensitive to pain (hyperalgesia) over time. There is also a long-standing notion that analgesic tolerance to opioids (habituation) develops during chronic use even though this phenomenon has never been prospectively studied. Our specific aims propose to prospectively test the hypotheses that; 1) Pain patients on chronic opioid therapy develop dose-dependent tolerance and/or hyperalgesia to these medications over time, 2) Opioid-induced tolerance and hyperalgesia develop differently with respect to various types of pain, 3) Opioid-induced hyperalgesia occurs independently of withdrawal phenomena, and 4) Opioid-induced tolerance and hyperalgesia develop differently based on gender and/or ethnicity. This proposed study will be the first quantitative and prospective study of tolerance and hyperalgesia in pain patients and will have important implications for the rational use of opioids in the treatment of chronic pain.
Stanford is currently not accepting patients for this trial. For more information, please contact Lawrence Chu, (650) 723 - 6411.
- Data Science for Digital Health and Precision Medicine
ANES 208A (Aut)
Independent Studies (7)
- Directed Reading in Anesthesiology
ANES 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Anesthesia
ANES 280 (Aut, Win, Spr, Sum)
- Graduate Research
ANES 399 (Aut, Win, Spr, Sum)
HUMBIO 194 (Win, Spr)
- Medical Scholars Research
ANES 370 (Aut, Win, Spr, Sum)
- Research in Human Biology
HUMBIO 193 (Aut, Win)
- Undergraduate Research
ANES 199 (Aut, Win, Spr, Sum)
- Directed Reading in Anesthesiology
Prior Year Courses
- Data Science for Digital Health and Precision Medicine
ANES 208A (Aut)
- Engage and Empower Me: Myths and Truths of Designing for Patient Behavior
ANES 205 (Aut)
- 3D Printing and Biofabrication
ANES 206 (Spr)
- Medical Education in the New Millenium: Innovation and Digital Disruption
ANES 204 (Aut)
- Data Science for Digital Health and Precision Medicine
Graduate and Fellowship Programs
Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy.
Journal of addiction medicine
Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans.In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]).Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ± 2.22, P < 0.0001; ΔSOWS = 12.48 ± 11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ± 2.39, P < 0.0001; ΔSOWS = 12.21 ± 10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores.We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.
View details for DOI 10.1097/ADM.0000000000000321
View details for PubMedID 28514235
Cytokine signature associated with disease severity in chronic fatigue syndrome patients.
Proceedings of the National Academy of Sciences of the United States of America
2017; 114 (34): E7150–E7158
Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine's preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.
View details for DOI 10.1073/pnas.1710519114
View details for PubMedID 28760971
View details for PubMedCentralID PMC5576836
Patient Participation at Health Care Conferences: Engaged Patients Increase Information Flow, Expand Propagation, and Deepen Engagement in the Conversation of Tweets Compared to Physicians or Researchers.
Journal of medical Internet research
2017; 19 (8): e280
Health care conferences present a unique opportunity to network, spark innovation, and disseminate novel information to a large audience, but the dissemination of information typically stays within very specific networks. Social network analysis can be adopted to understand the flow of information between virtual social communities and the role of patients within the network.The purpose of this study is to examine the impact engaged patients bring to health care conference social media information flow and how they expand dissemination and distribution of tweets compared to other health care conference stakeholders such as physicians and researchers.From January 2014 through December 2016, 7,644,549 tweets were analyzed from 1672 health care conferences with at least 1000 tweets who had registered in Symplur's Health Care Hashtag Project from 2014 to 2016. The tweet content was analyzed to create a list of the top 100 influencers by mention from each conference, who were then subsequently categorized by stakeholder group. Multivariate linear regression models were created using stepwise function building to identify factors explaining variability as predictor variables for the model in which conference tweets were taken as the dependent variable.Inclusion of engaged patients in health care conference social media was low compared to that of physicians and has not significantly changed over the last 3 years. When engaged patient voices are included in health care conferences, they greatly increase information flow as measured by total tweet volume (beta=301.6) compared to physicians (beta=137.3, P<.001), expand propagation of information tweeted during a conference as measured by social media impressions created (beta=1,700,000) compared to physicians (beta=270,000, P<.001), and deepen engagement in the tweet conversation as measured by replies to their tweets (beta=24.4) compared to physicians (beta=5.5, P<.001). Social network analysis of hubs and authorities revealed that patients had statistically significant higher hub scores (mean 8.26×10-4, SD 2.96×10-4) compared to other stakeholder groups' Twitter accounts (mean 7.19×10-4, SD 3.81×10-4; t273.84=4.302, P<.001).Although engaged patients are powerful accelerators of information flow, expanders of tweet propagation, and greatly deepen engagement in conversation of tweets on social media of health care conferences compared to physicians, they represent only 1.4% of the stakeholder mix of the top 100 influencers in the conversation. Health care conferences that fail to engage patients in their proceedings may risk limiting their engagement with the public, disseminating scientific information to a narrow community and slowing flow of information across social media channels.
View details for DOI 10.2196/jmir.8049
View details for PubMedID 28818821
View details for PubMedCentralID PMC5579322
Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study.
American journal of drug and alcohol abuse
Treatments for reducing opioid withdrawal are limited and prone to problematic side effects. Laboratory studies, clinical observations, and limited human trial data suggest 5-HT3-receptor antagonists and antihistamines may be effective.This double-blind, crossover, placebo-controlled study employing an acute physical dependence model evaluated whether (i) treatment with a 5-HT3-receptor antagonist (palonosetron) would reduce opioid withdrawal symptoms, and (ii) co-administration of an antihistamine (hydroxyzine) would enhance any treatment effect.At timepoint T = 0, healthy (non-opioid dependent, non-substance abuser) male volunteers (N = 10) were pre-treated with either a) placebo, b) palonosetron IV (0.75 mg), or c) palonosetron IV (0.75 mg) and hydroxyzine PO (100 mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10 mg/70kg). At T = 165, 10 mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = -30 and T = -15.Comparison of average baseline OOWS scores with OOWS scores obtained 15 minutes after naloxone was significant (p = 0.0001). Scores from 15 minutes post-naloxone infusion showed significant differences in OOWS scores between treatment groups: placebo, 3.7 ± 2.4; palonosetron, 1.5 ± 0.97; and palonosetron with hydroxyzine, 0.2 ± 0.1333.Pretreatment with palonosetron significantly reduced many signs of experimentally-induced opioid withdrawal. Co-administration with hydroxyzine further reduced opioid withdrawal severity. These results suggest that 5-HT3 receptor antagonists, alone or in combination with an antihistamine, may be useful in the treatment of opioid withdrawal.
View details for PubMedID 27712113
One Month of Oral Morphine Decreases Gray Matter Volume in the Right Amygdala of Individuals with Low Back Pain: Confirmation of Previously Reported Magnetic Resonance Imaging Results.
2016; 17 (8): 1497-1504
Prolonged exposure to opioids is known to produce neuroplastic changes in animals; however, few studies have investigated the effects of short-term prescription opioid use in humans. A previous study from our laboratory demonstrated a dosage-correlated volumetric decrease in the right amygdala of participants administered oral morphine daily for 1 month. The purpose of this current study was to replicate and extend the initial findings.Twenty-one participants with chronic low back pain were enrolled in this double-blind, placebo-controlled study. Participants were randomized to receive daily morphine (n = 11) or a matched placebo (n = 10) for 1 month. High-resolution anatomical images were acquired immediately before and after the treatment administration period. Morphological gray matter changes were investigated using tensor-based morphometry, and significant regions were subsequently tested for correlation with morphine dosage.Decreased gray matter volume was observed in several reward- and pain-related regions in the morphine group, including the bilateral amygdala, left inferior orbitofrontal cortex, and bilateral pre-supplementary motor areas. Morphine administration was also associated with significant gray matter increases in cingulate regions, including the mid cingulate, dorsal anterior cingulate, and ventral posterior cingulate.Many of the volumetric increases and decreases overlapped spatially with the previously reported changes. Individuals taking placebo for 1 month showed neither gray matter increases nor decreases. The results corroborate previous reports that rapid alterations occur in reward-related networks following short-term prescription opioid use.
View details for DOI 10.1093/pm/pnv047
View details for PubMedID 26814280
- Teaching the 21st Century Learner: Innovative Strategies and Practical Implementation. International anesthesiology clinics 2016; 54 (3): 35-53
Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study
The American Journal of Drug and Alcohol Abuse
View details for DOI 10.1080/00952990.2016.1210614
- "Nothing about us without us"-patient partnership in medical conferences. BMJ (Clinical research ed.) 2016; 354: i3883-?
Acute opioid withdrawal is associated with increased neural activity in reward-processing centers in healthy men: A functional magnetic resonance imaging study.
Drug and alcohol dependence
2015; 153: 314-322
Opioid analgesics are frequently prescribed for chronic pain. One expected consequence of long-term opioid use is the development of physical dependence. Although previous resting state functional magnetic resonance imaging (fMRI) studies have demonstrated signal changes in reward-associated areas following morphine administration, the effects of acute withdrawal on the human brain have been less well-investigated. In an earlier study by our laboratory, ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal. The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron.Ten participants were enrolled in this placebo-controlled, randomized, double-blind, crossover study and attended three acute opioid withdrawal sessions. Participants received either placebo or ondansetron (8Ymg IV) before morphine administration (10Ymg/70Ykg IV). Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan. Objective and subjective opioid withdrawal symptoms were assessed.Imaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions, including the right pregenual cingulate, putamen, and bilateral caudate, and decreased neural activity in networks involved in sensorimotor integration. Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal.This study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal. The fMRI acute opioid withdrawal model may serve as a tool for studying opioid dependence and withdrawal in human participants.
View details for DOI 10.1016/j.drugalcdep.2015.04.019
View details for PubMedID 26059463
The development of pediatric fluid resuscitation: an interview with Dr. Frederic A. 'Fritz' Berry
2014; 24 (2): 217-223
Dr. Frederic A. 'Fritz' Berry (1935), Professor Emeritus of Anesthesiology and Pediatrics at the University of Virginia, has played a pioneering role in the development of pediatric anesthesiology through training generations of anesthesiologists. He identifies his early advocacy of balanced electrolyte solution for perioperative fluid resuscitation as his defining contribution. Based on his clinical experiences, he pushed to extend the advances in adult fluid resuscitation into pediatric practice. He imparted these and other insights to his colleagues although textbooks, book chapters, original journal publications, and decades of Refresher Course Lectures at the American Society of Anesthesiologists' annual meetings. A model educator, clinician, and researcher, he shaped the careers of hundreds of physicians-in-training while advancing the field of pediatric anesthesiology.
View details for DOI 10.1111/pan.12309
View details for Web of Science ID 000329300800014
View details for PubMedID 24251450
RapidRead: step-at-a-glance crisis checklists
View details for DOI 10.4108/icst.pervasivehealth.2014.254954
Supporting crisis response with dynamic procedure aids
Proceedings of the 2014 conference on Designing interactive systems
View details for DOI 10.1145/2598510.2598565
The MOOClet Framework: Improving Online Education through Experimentation and Personalization of Modules
Social Science Research Network
View details for DOI 10.2139/ssrn.2523265
Videos in clinical medicine: Laryngeal mask airway in medical emergencies.
New England journal of medicine
2013; 369 (20)
This video demonstrates the placement of a laryngeal mask airway, an alternative airway device that is both efficacious and easy to place. The laryngeal mask airway is routinely used for patients receiving general anesthesia and, increasingly, in patient resuscitation.
View details for DOI 10.1056/NEJMvcm0909669
View details for PubMedID 24224639
- Laryngeal Mask Airway in Medical Emergencies NEW ENGLAND JOURNAL OF MEDICINE 2013; 369 (20)
Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology.
Journal of translational medicine
2013; 11: 93-?
Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity.Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days.Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.Our results support the role of cytokines in the pathophysiology of CFS.
View details for DOI 10.1186/1479-5876-11-93
View details for PubMedID 23570606
Interactive cognitive aids in medicine
CHI '13 Extended Abstracts on Human Factors in Computing Systems
View details for DOI 10.1145/2468356.2479562
Head-mounted and multi-surface displays support emergency medical teams
Proceedings of the 2013 conference on Computer supported cooperative work companion
View details for DOI 10.1145/2441955.2442020
- Clinical Anesthesiology Board Review edited by Chu, L. F. McGraw-Hill. 2013
Mobile computing in medical education: opportunities and challenges
CURRENT OPINION IN ANESTHESIOLOGY
2012; 25 (6): 699-718
There is an increasing importance of incorporating mobile computing into the academic medical environment. A growing majority of physicians, residents and medical students currently use mobile devices for education, access to clinical information and to facilitate bedside care. Therefore, it is important to assess the current opportunities and challenges in the use of mobile computing devices in the academic medical environment.Current research has found that a majority of physicians, residents and medical students either own or use mobile devices. In addition, studies have shown that these devices are effective as educational tools, resource guides and aids in patient care. Although there are opportunities for medical education, issues of deployment must still be addressed, such as privacy, connectivity, standardization and professionalism.Understanding the opportunities and challenges of using mobile computing devices in the academic medical environment can help determine the feasibility and benefits of their use for individuals and institutions.
View details for DOI 10.1097/ACO.0b013e32835a25f1
View details for Web of Science ID 000311030900012
View details for PubMedID 23103844
Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain
2012; 153 (8): 1583-1592
Although often successful in acute settings, long-term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently opioid-induced hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low-back pain were titrated to comfort or dose-limiting side effects in a prospective, randomized, double-blind, placebo-controlled clinical trial using sustained-release morphine or weight-matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine-treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop opioid-induced hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine-treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self-reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low-back pain developed tolerance but not opioid-induced hyperalgesia. Improvements in pain and functional ability were observed.
View details for DOI 10.1016/j.pain.2012.02.028
View details for Web of Science ID 000306240100011
View details for PubMedID 22704854
Modulation of remifentanil-induced postinfusion hyperalgesia by the beta-blocker propranolol in humans
2012; 153 (5): 974-981
Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the β(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the β-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. β-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.
View details for DOI 10.1016/j.pain.2012.01.014
View details for Web of Science ID 000302996200010
View details for PubMedID 22365565
Information technology and its role in anaesthesia training and continuing medical education.
Best practice & research. Clinical anaesthesiology
2012; 26 (1): 33-53
Today's educators are faced with substantial challenges in the use of information technology for anaesthesia training and continuing medical education. Millennial learners have uniquely different learning styles than previous generations of students. These preferences distinctly incorporate the use of digital information technologies and social technologies to support learning. To be effective teachers, modern educators must be familiar with these new information technologies and understand how to use them for medical education. Examples of new information technologies include learning management systems, lecture capture, social media (YouTube, Flickr), social networking (Facebook), Web 2.0, multimedia (video learning triggers and point-of-view video) and mobile computing applications. The information technology challenges for educators in the twenty-first century include: (a) understanding how technology shapes the learning preferences of today's anaesthesia residents, (b) distinguishing between the function and properties of new learning technologies and (c) properly using these learning technologies to enhance the anaesthesia curriculum.
View details for DOI 10.1016/j.bpa.2012.02.002
View details for PubMedID 22559955
Analysis of 4999 Online Physician Ratings Indicates That Most Patients Give Physicians a Favorable Rating
JOURNAL OF MEDICAL INTERNET RESEARCH
2011; 13 (4)
Many online physician-rating sites provide patients with information about physicians and allow patients to rate physicians. Understanding what information is available is important given that patients may use this information to choose a physician.The goals of this study were to (1) determine the most frequently visited physician-rating websites with user-generated content, (2) evaluate the available information on these websites, and (3) analyze 4999 individual online ratings of physicians.On October 1, 2010, using Google Trends we identified the 10 most frequently visited online physician-rating sites with user-generated content. We then studied each site to evaluate the available information (eg, board certification, years in practice), the types of rating scales (eg, 1-5, 1-4, 1-100), and dimensions of care (eg, recommend to a friend, waiting room time) used to rate physicians. We analyzed data from 4999 selected physician ratings without identifiers to assess how physicians are rated online.The 10 most commonly visited websites with user-generated content were HealthGrades.com, Vitals.com, Yelp.com, YP.com, RevolutionHealth.com, RateMD.com, Angieslist.com, Checkbook.org, Kudzu.com, and ZocDoc.com. A total of 35 different dimensions of care were rated by patients in the websites, with a median of 4.5 (mean 4.9, SD 2.8, range 1-9) questions per site. Depending on the scale used for each physician-rating website, the average rating was 77 out of 100 for sites using a 100-point scale (SD 11, median 76, range 33-100), 3.84 out of 5 (77%) for sites using a 5-point scale (SD 0.98, median 4, range 1-5), and 3.1 out of 4 (78%) for sites using a 4-point scale (SD 0.72, median 3, range 1-4). The percentage of reviews rated ≥75 on a 100-point scale was 61.5% (246/400), ≥4 on a 5-point scale was 57.74% (2078/3599), and ≥3 on a 4-point scale was 74.0% (740/1000). The patient's single overall rating of the physician correlated with the other dimensions of care that were rated by patients for the same physician (Pearson correlation, r = .73, P < .001).Most patients give physicians a favorable rating on online physician-rating sites. A single overall rating to evaluate physicians may be sufficient to assess a patient's opinion of the physician. The optimal content and rating method that is useful to patients when visiting online physician-rating sites deserves further study. Conducting a qualitative analysis to compare the quantitative ratings would help validate the rating instruments used to evaluate physicians.
View details for DOI 10.2196/jmir.1960
View details for Web of Science ID 000299313300040
View details for PubMedID 22088924
Prescription opioid analgesics rapidly change the human brain
2011; 152 (8): 1803-1810
Chronic opioid exposure is known to produce neuroplastic changes in animals; however, it is not known if opioids used over short periods of time and at analgesic dosages can similarly change brain structure in humans. In this longitudinal, magnetic resonance imaging study, 10 individuals with chronic low back pain were administered oral morphine daily for 1 month. High-resolution anatomical images of the brain were acquired immediately before and after the morphine administration period. Regional changes in gray matter volume were assessed on the whole brain using tensor-based morphometry, and those significant regional changes were then independently tested for correlation with morphine dosage. Thirteen regions evidenced significant volumetric change, and degree of change in several of the regions was correlated with morphine dosage. Dosage-correlated volumetric decrease was observed primarily in the right amygdala. Dosage-correlated volumetric increase was seen in the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons. Follow-up scans that were conducted an average of 4.7 months after cessation of opioids demonstrated many of the morphine-induced changes to be persistent. In a separate study, 9 individuals consuming blinded placebo capsules for 6 weeks evidenced no significant morphologic changes over time. The results add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward- and affect-processing circuitry. Morphologic changes occur rapidly in humans during new exposure to prescription opioid analgesics. Further research is needed to determine the clinical impact of those opioid-induced gray matter changes.
View details for DOI 10.1016/j.pain.2011.03.028
View details for Web of Science ID 000292862400020
View details for PubMedID 21531077
A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
2011; 400 (3): 715-728
Opioids such as morphine are the cornerstone of pain treatment. The challenge of measuring the concentrations of morphine and its active metabolites in order to assess human pharmacokinetics and monitor therapeutic drugs in children requires assays with high sensitivity in small blood volumes. We developed and validated a semi-automated LC-MS/MS assay for the simultaneous quantification of morphine and its active metabolites morphine 3β-glucuronide (M3G) and morphine 6β-glucuronide (M6G) in human plasma and in dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the internal standards were the only manual steps. Morphine and its metabolites were separated on a Kinetex 2.6-μm PFP analytical column using an acetonitrile/0.1% formic acid gradient. The analytes were detected in the positive multiple reaction mode. In plasma, the assay had the following performance characteristics: range of reliable response of 0.25-1000 ng/mL (r(2) > 0.99) for morphine, 1-1,000 ng/mL (r(2) > 0.99) for M3G, and 2.5-1,000 ng/mL for M6G. In DBS, the assay had a range of reliable response of 1-1,000 ng/mL (r(2) > 0.99) for morphine and M3G, and of 2.5-1,000 ng/mL for M6G. For inter-day accuracy and precision for morphine, M3G and M6G were within 15% of the nominal values in both plasma and DBS. There was no carryover, ion suppression, or matrix interferences. The assay fulfilled all predefined acceptance criteria, and its sensitivity using DBS samples was adequate for the measurement of pediatric pharmacokinetic samples using a small blood of only 20-50 μL.
View details for DOI 10.1007/s00216-011-4775-z
View details for Web of Science ID 000289297000015
View details for PubMedID 21400080
Self-Reported Information Needs of Anesthesia Residency Applicants and Analysis of Applicant-Related Web Sites Resources at 131 United States Training Programs
ANESTHESIA AND ANALGESIA
2011; 112 (2): 430-439
Despite the use of web-based information resources by both anesthesia departments and applicants, little research has been done to assess these resources and determine whether they are meeting applicant needs. Evidence is needed to guide anesthesia informatics research in developing high-quality anesthesia residency program Web sites (ARPWs).We used an anonymous web-based program (SurveyMonkey, Portland, OR) to distribute a survey investigating the information needs and perceived usefulness of ARPWs to all 572 Stanford anesthesia residency program applicants. A quantitative scoring system was then created to assess the quality of ARPWs in meeting the information needs of these applicants. Two researchers independently analyzed all 131 ARPWs in the United States to determine whether the ARPWs met the needs of applicants based on the scoring system. Finally, a qualitative assessment of the overall user experience of ARPWs was developed to account for the subjective elements of the Web site's presentation.Ninety-eight percent of respondents reported having used ARPWs during the application process. Fifty-six percent reported first visiting the Stanford ARPW when deciding whether to apply to Stanford's anesthesia residency program. Multimedia and Web 2.0 technologies were "very" or "most" useful in "learning intangible aspects of a program, like how happy people are" (42% multimedia and Web 2.0 versus 14% text and photos). ARPWs, on average, contained only 46% of the content items identified as important by applicants. The average (SD) quality scores among all ARPWs was 2.06 (0.59) of 4.0 maximum points. The mean overall qualitative score for all 131 ARPWs was 4.97 (1.92) of 10 points. Only 2% of applicants indicated that the majority (75%-100%) of Web sites they visited provided a complete experience.Anesthesia residency applicants rely heavily on ARPWs to research programs, prepare for interviews, and formulate a rank list. Anesthesia departments can improve their ARPWs by including information such as total hours worked and work hours by rotation (missing in 96% and 97% of ARPWs) and providing a valid web address on the Fellowship and Residency Electronic Interactive Database Access System (FREIDA) (missing in 28% of ARPWs).
View details for DOI 10.1213/ANE.0b013e3182027a94
View details for Web of Science ID 000286576000023
View details for PubMedID 21081766
The Endogenous Opioid System Is Not Involved in Modulation of Opioid-Induced Hyperalgesia
JOURNAL OF PAIN
2011; 12 (1): 108-115
Some recent studies suggested a role of the endogenous opioid system in modulating opioid-induced hyperalgesia (OIH). In order to test this hypothesis, we conducted a prospective randomized, placebo-controlled, 2-way crossover study in healthy human volunteers. We utilized a well-established model of inducing OIH after a brief exposure to the μ-opioid agonist remifentanil using intradermal electrical stimulation. Patients were exposed to a randomized 90-minute infusion of remifentanil or saline placebo during 2 separate occasions. Development of OIH was quantified using changes in the average radius of the area of secondary hyperalgesia generated by electrical pain stimulation. A 23.6% (20.2) increase in area of secondary hyperalgesia over baseline was observed in the postinfusion period of the remifentanil session, demonstrating development of OIH (P = .03). In order to test endogenous opioid system modulation of OIH, patients were given a 1-time bolus of naloxone, which had no effect on the size of the hyperalgesic lesion in either the remifentinal or placebo session. These results suggested that the endogenous opioid system did not appear to modulate OIH.Experimental evidence suggested that the endogenous opioid system did not significantly affect opioid-induced hyperalgesia. Consequently, this study suggested that alternative mechanisms such as pronociceptive stimulation and neuroplastic changes might be responsible for expression of OIH.
View details for DOI 10.1016/j.jpain.2010.05.006
View details for Web of Science ID 000286549700013
View details for PubMedID 20864417
- A visual guide to anesthesia procedures LWW. 2011
- Coagulopathies Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- A visual guide to regional anesthesia LWW. 2011
- Wire Crichothyroidotomy Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Endotracheal Intubation Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
Maintaining shared mental models in anesthesia crisis care with nurse tablet input and large-screen displays
Proceedings of the 24th annual ACM symposium adjunct on User interface software and technology
View details for DOI 10.1145/2046396.2046428
- Mask Ventilation Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Insertion of Peripheral IV Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- The Anesthetic Plan and Induction of Anesthesia Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Radial Artery Catheterization Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Insertion of Left-Sided DLT Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Awake Fiber Optic Intubation Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Spinal Anesthesia Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- A visual guide to transesophageal echocardiography LWW. 2011
- A visual guide to crisis management LWW. 2011
- Standard Induction of GA Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Laryngeal Mask Airway Insertion Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Lumbar Epidural Placement Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Central Venous Catheterization Manual of Clinical Anesthesiology Lippincott Williams and Wilkins. 2011
- Manual of Clinical Anesthesiology edited by Chu, L. F., Fuller, A. J. LWW. 2011
Learning management systems and lecture capture in the medical academic environment.
International anesthesiology clinics
2010; 48 (3): 27-51
As residents work disparate schedules at multiple locations and because of workweek hour limits mandated by the ACGME, residents may be unable to attend lectures, seminars, or other activities that would enhance their skills. Further, the ACGME requires that residency programs document resident learning in six stated core competencies and provide proof of completion for various other requirements. LMS/LC is a promising technology to provide a means by which residency programs may overcome these obstacles. More studies are needed to show under what conditions an LMS/LC program actually enhances learning, and which elements are most useful to the new generation of learners comfortable with Web 2.0 technologies.
View details for DOI 10.1097/AIA.0b013e3181e5c1d5
View details for PubMedID 20616636
- The role of social networking applications in the medical academic environment. International anesthesiology clinics 2010; 48 (3): 61-82
Finite element modeling of subcutaneous implantable defibrillator electrodes in an adult torso
2010; 7 (5): 692-698
Total subcutaneous implantable subcutaneous defibrillators are in development, but optimal electrode configurations are not known.We used image-based finite element models (FEM) to predict the myocardial electric field generated during defibrillation shocks (pseudo-DFT) in a wide variety of reported and innovative subcutaneous electrode positions to determine factors affecting optimal lead positions for subcutaneous implantable cardioverter-defibrillators (S-ICD).An image-based FEM of an adult man was used to predict pseudo-DFTs across a wide range of technically feasible S-ICD electrode placements. Generator location, lead location, length, geometry and orientation, and spatial relation of electrodes to ventricular mass were systematically varied. Best electrode configurations were determined, and spatial factors contributing to low pseudo-DFTs were identified using regression and general linear models.A total of 122 single-electrode/array configurations and 28 dual-electrode configurations were simulated. Pseudo-DFTs for single-electrode orientations ranged from 0.60 to 16.0 (mean 2.65 +/- 2.48) times that predicted for the base case, an anterior-posterior configuration recently tested clinically. A total of 32 of 150 tested configurations (21%) had pseudo-DFT ratios =1, indicating the possibility of multiple novel, efficient, and clinically relevant orientations. Favorable alignment of lead-generator vector with ventricular myocardium and increased lead length were the most important factors correlated with pseudo-DFT, accounting for 70% of the predicted variation (R(2) = 0.70, each factor P < .05) in a combined general linear model in which parameter estimates were calculated for each factor.Further exploration of novel and efficient electrode configurations may be of value in the development of the S-ICD technologies and implant procedure. FEM modeling suggests that the choice of configurations that maximize shock vector alignment with the center of myocardial mass and use of longer leads is more likely to result in lower DFT.
View details for DOI 10.1016/j.hrthm.2010.01.030
View details for Web of Science ID 000277354400024
View details for PubMedID 20230927
Anesthesia 2.0: Internet-based information resources and Web 2.0 applications in anesthesia education
CURRENT OPINION IN ANESTHESIOLOGY
2010; 23 (2): 218-227
Informatics is a broad field encompassing artificial intelligence, cognitive science, computer science, information science, and social science. The goal of this review is to illustrate how Web 2.0 information technologies could be used to improve anesthesia education.Educators in all specialties of medicine are increasingly studying Web 2.0 technologies to maximize postgraduate medical education of housestaff. These technologies include microblogging, blogs, really simple syndication (RSS) feeds, podcasts, wikis, and social bookmarking and networking. 'Anesthesia 2.0' reflects our expectation that these technologies will foster innovation and interactivity in anesthesia-related web resources which embraces the principles of openness, sharing, and interconnectedness that represent the Web 2.0 movement. Although several recent studies have shown benefits of implementing these systems into medical education, much more investigation is needed.Although direct practice and observation in the operating room are essential, Web 2.0 technologies hold great promise to innovate anesthesia education and clinical practice such that the resident learner need not be in a classroom for a didactic talk, or even in the operating room to see how an arterial line is properly placed. Thoughtful research to maximize implementation of these technologies should be a priority for development by academic anesthesiology departments. Web 2.0 and advanced informatics resources will be part of physician lifelong learning and clinical practice.
View details for DOI 10.1097/ACO.0b013e328337339c
View details for Web of Science ID 000275817300015
View details for PubMedID 20090518
Bilateral infraorbital nerve blocks decrease postoperative pain but do not reduce time to discharge following outpatient nasal surgery
Annual Meeting of the American-Society-of-Anesthesiologist
SPRINGER. 2009: 584–89
While infraorbital nerve blocks have demonstrated analgesic benefits for pediatric nasal and facial plastic surgery, no studies to date have explored the effect of this regional anesthetic technique on adult postoperative recovery. We designed this study to test the hypothesis that infraorbital nerve blocks combined with a standardized general anesthetic decrease the duration of recovery following outpatient nasal surgery.At a tertiary care university hospital, healthy adult subjects scheduled for outpatient nasal surgery were randomly assigned to receive bilateral infraorbital injections with either 0.5% bupivacaine (Group IOB) or normal saline (Group NS) using an intraoral technique immediately following induction of general anesthesia. All subjects underwent a standardized general anesthetic regimen and were transported to the recovery room following tracheal extubation. The primary outcome was the duration of recovery (minutes) from recovery room admission until actual discharge to home. Secondary outcomes included average and worst pain scores, nausea and vomiting, and supplemental opioid requirements.Forty patients were enrolled. A statistically significant difference in mean [SD] recovery room duration was not observed between Groups IOB and NS (131  min vs 133  min, respectively; P = 0.77). Subjects in Group IOB did experience a reduction in average pain on a 0-100 mm scale (mean [95% confidence interval]) compared to Group NS (-11 [-21 to 0], P = 0.047), but no other comparison of secondary outcomes was statistically significant.When added to a standardized general anesthetic, bilateral IOB do not decrease actual time to discharge following outpatient nasal surgery despite a beneficial effect on postoperative pain.
View details for DOI 10.1007/s12630-009-9119-5
View details for Web of Science ID 000268294300005
View details for PubMedID 19475468
Anesthesia-controlled time and turnover time for ambulatory upper extremity surgery performed with regional versus general anesthesia
31st Annual Spring Meeting of the American-Society-of-Regional-Anesthesia-and-Pain-Medicine
ELSEVIER SCIENCE INC. 2009: 253–57
To test the hypothesis that regional anesthesia (RA) employing a block room reduces anesthesia-controlled time for ambulatory upper extremity surgery compared with general anesthesia (GA).Retrospective cohort study.Outpatient surgery center of a university hospital.229 adult patients who underwent ambulatory upper extremity surgery over one year.Upper extremity surgery was performed with three different anesthetic techniques: 1) GA, 2) nerve block (NB) performed preoperatively, or 3) local anesthetic (LA), either Bier block or local anesthetic, administered in the operating room (OR).Demographic data, anesthesia-controlled time, and turnover time were recorded. Since the data were not normally distributed, differences in anesthesia-controlled time and turnover time were analyzed using the Kruskal-Wallis test and post-hoc testing using one-way analysis of variance on the ranks of the observations, with Tukey-Kramer correction for multiple comparisons.Anesthesia-controlled time for NB (median 28 min) was significantly shorter than for GA (median 32 min, P = 0.0392). Anesthesia-controlled time for patients who received LA (median 25 min) was also significantly shorter than GA (P < 0.0001). However, turnover time did not differ significantly among the three groups.Peripheral nerve block performed preoperatively in an induction area or LA injected in the OR significantly reduces anesthesia-controlled time for ambulatory upper extremity surgery compared with GA. Turnover time is unaffected by anesthetic technique. These results may increase acceptance of RA in the ambulatory surgery setting.
View details for DOI 10.1016/j.jclinane.2008.08.019
View details for Web of Science ID 000267501500004
View details for PubMedID 19502033
No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans
2009; 142 (1-2): 17-26
It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in "acute tolerance." The aim of this double-blind, placebo-controlled study in thirty-six healthy human volunteers was to examine whether a 3-h intravenous infusion delivering two different but clinically relevant doses of the mu-opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3-h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3-h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady-state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3-h infusion. The study was adequately powered to detect a decrease in potency of 5-24% for analgesia, 20-48% for respiratory depression, and 32% for sedative effects. These results suggest that short-term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects.
View details for DOI 10.1016/j.pain.2008.11.001
View details for Web of Science ID 000264275800008
View details for PubMedID 19135798
From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics
PHARMACOGENETICS AND GENOMICS
2009; 19 (3): 193-205
Addiction to opioid narcotics represents a major public health challenge. Animal models of one component of addiction, physical dependence, show this trait to be highly heritable. The analysis of opioid dependence using contemporary in-silico techniques offers an approach to discover novel treatments for dependence and addiction.In these experiments, opioid withdrawal behavior in 18 inbred strains of mice was assessed. Mice were treated for 4 days with escalating doses of morphine before the administration of naloxone allowing the quantification of opioid dependence. After haplotypic analysis, experiments were designed to evaluate the top gene candidate as a modulator of physical dependence. Behavioral studies as well as measurements of gene expression on the mRNA and protein levels were completed. Finally, a human model of opioid dependence was used to quantify the effects of the 5-HT3 antagonist ondansetron on signs and symptoms of withdrawal.The Htr3a gene corresponding to the 5-HT3 receptor emerged as the leading candidate. Pharmacological studies using the selective 5-HT3 antagonist ondansetron supported the link in mice. Morphine strongly regulated the expression of the Htr3a gene in various central nervous system regions including the amygdala, dorsal raphe, and periaqueductal gray nuclei, which have been linked to opioid dependence in previous studies. Using an acute morphine administration model, the role of 5-HT3 in controlling the objective signs of withdrawal in humans was confirmed.These studies show the power of in-silico genetic mapping, and reveal a novel target for treating an important component of opioid addiction.
View details for DOI 10.1097/FPC.0b013e328322e73d
View details for Web of Science ID 000264169500002
View details for PubMedID 19214139
- Overview on Clinical Features of Opioid-Induced Hyperalgesia. Opioid-Induced Hyperalgesia. 2009: 21-37
- Molecular basis and clinical implications of opioid tolerance and opioid-induced hyperalgesia Acute Pain Management Cambridge University Press. 2009; 1: 114–146
- Ondansetron: an effective treatment for the withdrawal symptoms of opioids? Therapy 2009; 6 (5): 637-640
- Molecular Basis and Clinical Implications of Opioid Tolerance and Opioid-induced Hyperalgesia Acute Pain Management, Cambridge University Press, New York, New York 2009
Reduced Cold Pain Tolerance in Chronic Pain Patients Following Opioid Detoxification
2008; 9 (8): 1158-1163
One potential consequence of chronic opioid analgesic administration is a paradoxical increase of pain sensitivity over time. Little scientific attention has been given to how cessation of opioid medication affects the hyperalgesic state. In this study, we examined the effects of opioid tapering on pain sensitivity in chronic pain patients.Twelve chronic pain patients on long-term opioid analgesic treatment were observed in a 7- to 14-day inpatient pain rehabilitation program, with cold pain tolerance assessed at admission and discharge. The majority of participants were completely withdrawn from their opioids during their stay.We hypothesized that those patients with the greatest reduction in daily opioid use would show the greatest increases in pain tolerance, as assessed by a cold pressor task.A linear regression revealed that the amount of opioid medication withdrawn was a significant predictor of pain tolerance changes, but not in the direction hypothesized. Greater opioid reduction was associated with decreased pain tolerance. This reduction of pain tolerance was not associated with opioid withdrawal symptoms or changes in general pain.These findings suggest that the withdrawal of opioids in a chronic pain sample leads to an acute increase in pain sensitivity.
View details for DOI 10.1111/j.1526-4637.2008.00475.x
View details for Web of Science ID 000261106100026
View details for PubMedID 18564998
Opioid-induced hyperalgesia in humans - Molecular mechanisms and clinical considerations
CLINICAL JOURNAL OF PAIN
2008; 24 (6): 479-496
Opioid-induced hyperalgesia (OIH) is most broadly defined as a state of nociceptive sensitization caused by exposure to opioids. The state is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain may actually become more sensitive to certain painful stimuli. The type of pain experienced may or may not be different from the original underlying painful condition. Although the precise molecular mechanism is not yet understood, it is generally thought to result from neuroplastic changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive pathways. OIH seems to be a distinct, definable, and characteristic phenomenon that may explain loss of opioid efficacy in some cases. Clinicians should suspect expression of OIH when opioid treatment effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the pain as previously observed. This review highlights the important mechanistic underpinnings and clinical ramifications of OIH and discusses future research directions and the latest clinical evidence for modulation of this potentially troublesome clinical phenomenon.
View details for Web of Science ID 000257198800003
View details for PubMedID 18574358
Comparative evaluation of noninvasive compression adjuncts for hemostasis in percutaneous arterial, venous, and arteriovenous dialysis access procedures
JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
2008; 19 (1): 72-79
To assess the relative efficacy of three compression adjuncts -- D-Stat Dry (D-Stat), QR Powder (QR), and XS Powder (XS) -- for reducing time to hemostasis in patients who underwent diagnostic and interventional percutaneous procedures.D-Stat, QR, or XS was applied in 176 percutaneous diagnostic arterial, therapeutic arterial, venous, and arteriovenous dialysis access (AVDA) procedures in 138 patients. The mean time to hemostasis and application-related complications were retrospectively assessed.Mean time to hemostasis was significantly reduced in all applications of QR (3.1 minutes +/- 1.1) and XS (3.7 minutes +/- 1.1) relative to D-Stat (6.2 minutes +/- 1.1, P < .001 vs both). For therapeutic arterial procedures, mean time to hemostasis for QR and XS was 3.6 minutes +/- 1.1 and 4.8 minutes +/- 1.1, respectively, and this was significantly less than that of D-Stat (10.0 minutes +/- 1.2; P < .001 vs QR, P < .01 vs XS). Mean times to hemostasis for QR and XS were also shorter than that with D-Stat in diagnostic arterial and AVDA procedures (P < .05). For venous procedures, mean time to hemostasis for QR (1.9 minutes +/- 1.2) was significantly shorter than that with both D-Stat (4.0 minutes +/- 1.2, P < .05) and XS (3.7 minutes +/- 1.2, P < .05). Minor immediate complications (hematoma <5 cm) occurred in 2.8% of applications. No access site infections were observed.All three agents effectively reduced time to hemostasis with minimal associated complications. QR was found to be more effective than D-Stat in all four procedure types.
View details for DOI 10.1016/j.jvir.2007.08.028
View details for Web of Science ID 000252853200012
View details for PubMedID 18192470
- Comparison of supplementation rates for perivascular axillary and coracoid infraclavicular blocks in ambulatory upper extremity surgery. Ambulatory Surgery 2008; 14 (2): 95-109
Ketamine does not increase pulmonary vascular resistance in children with pulmonary hypertension undergoing sevoflurane anesthesia and spontaneous ventilation
ANESTHESIA AND ANALGESIA
2007; 105 (6): 1578-1584
The use of ketamine in children with increased pulmonary vascular resistance is controversial. In this prospective, open label study, we evaluated the hemodynamic responses to ketamine in children with pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg).Children aged 3 mo to 18 yr with pulmonary hypertension, who were scheduled for cardiac catheterization with general anesthesia, were studied. Patients were anesthetized with sevoflurane (1 minimum alveolar anesthetic concentration [MAC]) in air while breathing spontaneously via a facemask. After baseline catheterization measurements, sevoflurane was reduced (0.5 MAC) and ketamine (2 mg/kg IV over 5 min) was administered, followed by a ketamine infusion (10 microg x kg(-1) x min(-1)). Catheterization measurements were repeated at 5, 10, and 15 min after completion of ketamine load. Data at various time points were compared (ANOVA, P < 0.05).Fifteen patients (age 147, 108 mo; median, interquartile range) were studied. Diagnoses included idiopathic pulmonary arterial hypertension (5), congenital heart disease (9), and diaphragmatic hernia (1). At baseline, median (interquartile range) baseline pulmonary vascular resistance index was 11.3 (8.2) Wood units; 33% of patients had suprasystemic mean pulmonary artery pressures. Heart rate (99, 94 bpm; P = 0.016) and Pao2 (95, 104 mm Hg; P = 007) changed after ketamine administration (baseline, 15 min after ketamine; P value). There were no significant differences in mean systemic arterial blood pressure, mean pulmonary artery pressure, systemic or pulmonary vascular resistance index, cardiac index, arterial pH, or Paco2.In the presence of sevoflurane, ketamine did not increase pulmonary vascular resistance in spontaneously breathing children with severe pulmonary hypertension.
View details for DOI 10.1213/01.ane.0000287656.29064.89
View details for Web of Science ID 000251274400014
View details for PubMedID 18042853
Single-dose, extended-release epidural morphine (DepoDur (TM)) compared to conventional epidural morphine for post-cesarean pain
ANESTHESIA AND ANALGESIA
2007; 105 (1): 176-183
A single-dose of neuraxial morphine sulfate provides good post-Cesarean analgesia; however, its efficacy is limited to the first postoperative day. In a recent phase III study, extended-release epidural morphine (EREM) formulation provided more effective, prolonged analgesia after Cesarean delivery, compared to conventional epidural morphine. However, the study protocol did not allow for the use of nonsteroidal antiinflammatory drugs, used various postoperative analgesics, and monitoring and treatment of respiratory depression were not standardized. Our aims in this study were to compare postoperative analgesic consumption, pain scores and side effects of EREM with conventional morphine for the management of post-Cesarean pain in a setting more reflective of current obstetric practice.Seventy healthy parturients undergoing elective Cesarean delivery were enrolled in this randomized, double-blind study. Using a combined spinal epidural technique, patients received an intrathecal injection of bupivacaine 12 mg and fentanyl 10 mcg. After closure of the fascia, a single-dose of either conventional morphine 4 mg or EREM 10 mg was administered epidurally. Postoperatively, all patients received ibuprofen 600 mg orally every 6 h. Oral oxycodone and IV morphine were available for breakthrough pain. All patients received pulse oximetry and respiratory monitoring for 48 h post-Cesarean delivery.Single-dose EREM significantly improved pain scores at rest and during activity. The median (interquartile range) of supplemental opioid medication usage for 48 h post-Cesarean (in milligram-morphine equivalents) decreased from 17 (22) to 10 (17) mg with EREM compared to conventional epidural morphine (P = 0.037). Both drugs were well tolerated with no significant difference in adverse event profiles.EREM provides superior and prolonged post-Cesarean analgesia compared to conventional epidural morphine with no significant increases in adverse events.
View details for DOI 10.1213/01.ane.0000265533.13477.26
View details for Web of Science ID 000247444800032
View details for PubMedID 17578973
Modified and conventional ultrafiltration during pediatric cardiac surgery: Clinical outcomes compared
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
2006; 132 (6): 1291-1298
This prospective study compared clinical outcomes after heart surgery between three groups of infants with congenital heart disease. One group received dilutional conventional ultrafiltration (group D), another received modified ultrafiltration (group M), and a third group received both dilutional conventional and modified ultrafiltration (group B). We hypothesized that group B patients would have the best clinical outcome.Children younger than 1 year undergoing heart surgery for biventricular repair by the same surgeon were randomly allocated to one of the three study groups. Patient management was standardized, and intensive care staff were blinded to group allocation. Primary outcome measure was duration of postoperative mechanical ventilation. Other outcome measures recorded included total blood products transfused, duration of chest tube in situ, chest tube output, and stays in intensive care and in the hospital.Sixty infants completed study protocol. Mean age and weight were as follows: group D (n = 19), 61 days, 4.3 kg; group M (n = 20), 64 days, 4.5 kg; and group B (n = 21), 86 days, 4.4 kg. Preoperative and intraoperative characteristics were similar between groups. Ultrafiltrate volumes obtained were 196 +/- 93 mL/kg in group D, 105 +/- 33 mL/kg in group M, and 261 +/- 113 mL/kg in group B. There were no significant differences between groups for any outcome variable. Technical difficulties prevented completion of modified ultrafiltration in 2 of 41 infants.There was no clinical advantage in combining conventional and modified ultrafiltration. Because clinical outcomes were similar across groups, relative risks of the ultrafiltration strategies may influence choice.
View details for DOI 10.1016/j.jtcvs.2006.05.059
View details for Web of Science ID 000242626200010
View details for PubMedID 17140945
Scheduling elective pediatric procedures that require anesthesia: The perspective of parents
ANESTHESIA AND ANALGESIA
2006; 103 (6): 1426-1431
Daily variability in volume of elective pediatric procedures that require anesthesia may lead to an imbalance between available operating room resources and case load. Longer intervals between scheduling and the surgical date generally result in higher operating room utilization. In this study, we sought to determine which factors influence when parents schedule their children for procedures. We also aimed to identify parents' ideal and longest acceptable waiting intervals and determine whether type of procedure, for example, affects scheduling. From a convenience sample of 250 randomly selected parents of children presenting for elective surgery, 236 completed surveys were analyzed. The remaining 14 surveys were not returned. Overall, parents scheduled their child's procedure a median of 4.3 wk (interquartile range 2.0-8.6) in advance and reported an ideal waiting interval of 3 wk (interquartile range 2-4), and longest acceptable interval of 6 wk (interquartile range 4-10). Parents were willing to wait longer to schedule cardiac (4 wk, P = 0.004) and plastic (3.5 wk, P = 0.024) surgery when compared with general surgical procedures. Overall, parents ranked severity of the child's illness, earliest available time, and surgeon's suggested date as the three most important factors influencing when their child's surgery is scheduled. The timetable for scheduling procedures was highly correlated with both mother and father having available time off work (tau(b) = 0.72, P < 0.0001). Surprisingly, parents did not show a preference for scheduling cases during vacation or summer months.
View details for DOI 10.1213/01.ane.0000244596.03605.3e
View details for Web of Science ID 000242289100019
View details for PubMedID 17122217
Valdecoxib for postoperative pain management after cesarean delivery: A randomized, double-blind, placebo-controlled study
37th Annual Meeting of the Society-for-Obstetric-Anesthesia-and-Perinatology
LIPPINCOTT WILLIAMS & WILKINS. 2006: 664–70
Although nonsteroidal antiinflammatory drugs (NSAIDs) improve postoperative pain relief after cesarean delivery, they carry potential side effects (e.g., bleeding). Perioperative cyclooxygenase (COX)-2 inhibitors show similar analgesic efficacy to nonsteroidal antiinflammatory drugs in many surgical models but have not been studied after cesarean delivery. We designed this randomized double-blind study to determine the analgesic efficacy and opioid-sparing effects of valdecoxib after cesarean delivery. Healthy patients undergoing elective cesarean delivery under spinal anesthesia were randomized to receive oral valdecoxib 20 mg or placebo every 12 h for 72 h postoperatively. As a result of cyclooxygenase-2 inhibitors safety concerns that became apparent during this study, the study was terminated early after evaluating 48 patients. We found no differences in total analgesic consumption between the valdecoxib and placebo groups (121 +/- 70 versus 143 +/- 77 morphine mg-equivalents, respectively; P = 0.26). Pain at rest and during activity were similar between the groups despite adequate post hoc power to have detected a clinically significant difference. There were also no differences in IV morphine requirements, time to first analgesic request, patient satisfaction, side effects, breast-feeding success, or functional activity. Postoperative pain was generally well controlled. Adding valdecoxib after cesarean delivery under spinal anesthesia with intrathecal morphine is not supported at this time.
View details for DOI 10.1213/01.ane.0000229702.42426.a6
View details for Web of Science ID 000240049800025
View details for PubMedID 16931678
Communication in critical care environments: Mobile telephones improve patient care
ANESTHESIA AND ANALGESIA
2006; 102 (2): 535-541
Most hospital policies prohibiting the use of wireless devices cite reports of disruption of medical equipment by cellular telephones. There have been no studies to determine whether mobile telephones may have a beneficial impact on safety. At the 2003 meeting of the American Society of Anesthesiologists 7878 surveys were distributed to attendees. The five-question survey polled anesthesiologists regarding modes of communication used in the operating room/intensive care unit and experience with communications delays and medical errors. Survey reliability was verified using test-retest analysis and proportion agreement in a convenience sample of 17 anesthesiologists. Four-thousand-eighteen responses were received. The test-retest reliability of the survey instrument was excellent (Kappa = 0.75; 95% confidence interval, 0.56-0.94). Sixty-five percent of surveyed anesthesiologists reported using pagers as their primary mode of communications, whereas only 17% used cellular telephones. Forty-five percent of respondents who use pagers reported delays in communications compared with 31% of cellular telephone users. Cellular telephone use by anesthesiologists is associated with a reduction in the risk of medical error or injury resulting from communication delay (relative risk = 0.78; 95% confidence interval, 0.6234-0.9649). The small risks of electromagnetic interference between mobile telephones and medical devices should be weighed against the potential benefits of improved communication.
View details for DOI 10.1213/01.ane.0000194506.79408.79
View details for Web of Science ID 000234912900040
View details for PubMedID 16428557
Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study
JOURNAL OF PAIN
2006; 7 (1): 43-48
There is accumulating evidence that opioid therapy might not only be associated with the development of tolerance but also with an increased sensitivity to pain, a condition referred to as opioid-induced hyperalgesia (OIH). However, there are no prospective studies documenting the development of opioid tolerance or OIH in patients with chronic pain. This preliminary study in 6 patients with chronic low back pain prospectively evaluated the development of tolerance and OIH. Patients were assessed before and 1 month after initiating oral morphine therapy. The cold pressor test and experimental heat pain were used to measure pain sensitivity before and during a target-controlled infusion with the short-acting mu opioid agonist remifentanil. In the cold pressor test, all patients became hyperalgesic as well as tolerant after 1 month of oral morphine therapy. In a model of heat pain, patients exhibited no hyperalgesia, although tolerance could not be evaluated. These results provide the first prospective evidence for the development of analgesic tolerance and OIH by using experimental pain in patients with chronic back pain. This study also validated methodology for prospectively studying these phenomena in larger populations of pain patients.Experimental evidence suggests that opioid tolerance and opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain. This study validates a pharmacologic approach to study these phenomena prospectively in chronic pain patients and suggests that both conditions do occur within 1 month of initiating opioid therapy.
View details for DOI 10.1016/j.jpain.2005.08.001
View details for Web of Science ID 000235142300008
View details for PubMedID 16414554
Successful thoracoscopic repair of esophageal atresia with tracheoesophageal fistula in a newborn with single ventricle physiology
ANESTHESIA AND ANALGESIA
2005; 101 (4): 1000-1002
A neonate with VACTERL association including tricuspid atresia was scheduled for thoracoscopic esophageal atresia with tracheoesophageal fistula (EA/TEF) repair and laparoscopic gastrostomy tube placement. In addition to standard noninvasive monitoring, arterial blood pressure, central venous pressure, and cerebral oxygen saturation were monitored. Gastric distension resulting from positive pressure ventilation prevented laparoscopic gastrostomy tube placement. Thoracoscopy with a CO2 insufflation pressure of 6 mm Hg at low flow (1 L/min) was well tolerated hemodynamically despite hypercarbia and cerebral oxygen saturation was maintained. Careful monitoring and good communication were critical to the safe management of this single ventricle patient during thoracoscopic EA/TEF repair.Esophageal and tracheoesophageal fistula in conjunction with single ventricle physiology carries a significant risk of mortality. We present the anesthetic management of a neonate with unpalliated tricuspid atresia who underwent thoracoscopic tracheoesophageal fistula repair.
View details for DOI 10.1213/01.ANE.0000175778.96374.4F
View details for Web of Science ID 000232115400011
View details for PubMedID 16192508
A comparison of three methods for estimating appropriate tracheal tube depth in children
2005; 15 (10): 846-851
Estimating appropriate tracheal tube (TT) depth following tracheal intubation in infants and children presents a challenge to anesthesia practitioners. We evaluated three methods commonly used by anesthesiologists to determine which one most reliably results in appropriate positioning.After IRB approval, 60 infants and children scheduled for fluoroscopic procedures requiring general anesthesia were enrolled. Patients were randomly assigned to one of three groups: (1) deliberate mainstem intubation with subsequent withdrawal of the TT 2 cm above the carina ('mainstem' method); (2) alignment of the double black line marker near the TT tip at the vocal cords ('marker' method); or (3) placement of the TT at a depth determined by the formula: TT depth (cm) = 3 x TT size (mmID) ('formula' method). TT tip position was determined to be 'appropriate' if located between the sternoclavicular junction (SCJ) and 0.5 cm above the carina as determined by fluoroscopy. Risk ratios were calculated, and data were analysed by the chi-square test accepting statistical significance at P < 0.05.The mainstem method was associated with the highest rate of appropriate TT placement (73%) compared with both the marker method (53%, P = 0.03, RR = 1.56) and the formula method (42%, P = 0.006, RR = 2.016). There was no difference between the marker and formula methods overall (P = 0.2, RR = 1.27). Analysis of age-stratified data demonstrated higher success with the marker method compared with the formula method for patients 3-12 months (P = 0.0056, RR = 4.0).Deliberate mainstem intubation most reliably results in appropriate TT depth in infants and children.
View details for DOI 10.1111/j.1460-9592.2005.01577.x
View details for Web of Science ID 000232471900005
View details for PubMedID 16176312
- Clinical Anesthesiology Board Review McGraw-Hill Medical Publishing 2005
Different molecular forms of uncomplexed prostate specific antigen (PSA) show similar immunoreactivities
JOURNAL OF UROLOGY
1999; 161 (6): 2009-2012
PSA exists in multiple molecular forms in serum, with the majority complexed to proteinase inhibitors such as alpha 1-antichymotrypsin and alpha 2-macroglobulin. The uncomplexed, or "free" forms of PSA represent a very heterogenous distribution of molecular isoforms. It has been suggested that these variations in uncomplexed PSA may cause differences in their immunologic characteristics which may lead to analytical differences between various PSA assays. We report that various isoforms of uncomplexed PSA purified from seminal fluid as previously described show no differences in relative immunoreactivity and demonstrate equimolar behavior as measured by the TOSOH AIA-600 assay, which is a PSA assay based upon monoclonal PSA and monoclonal detecting antibodies (mono-mono). Furthermore, we show that carbohydrate side-chain modification does not change the equimolar immunoreactivity of these isoforms.
View details for Web of Science ID 000080202500083
View details for PubMedID 10332491
Evolution of web site design: implications for medical education on the Internet
COMPUTERS IN BIOLOGY AND MEDICINE
1998; 28 (5): 459-472
Since its inception, the world wide web (WWW) has possessed the potential for becoming a 'watershed' medium for conveying complex, structured information across vast temporal and geographical barriers. In 1995, the MedWorld project (http:(/)/medworld.stanford.edu) was created at the Stanford University School of Medicine in an effort to innovate and explore the design process of creating WWW applications specifically for medical education. Until recently, the evolution of WWW applications has been mainly driven by technological advances in client-server technology, enabling or translating traditional modes of collaborative medical education (e.g. voice, presence, print, motion) into WWW devices and applications. Many of these applications, while technologically advanced, lack focused development of interface and interactivity design, which may enhance learning experiences. WWW applications which incorporate design innovation in parity with advances in client-server technology have been termed, 'third generation' web sites and have the potential to improve the quality of WWW applications designed for medical education. This work describes how the MedWorld project has created a 'third generation' WWW application by utilizing innovation in information, interface and interactivity design to create innovative WWW technology for the medical education arena.
View details for Web of Science ID 000077407500002
View details for PubMedID 9861505
Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM
1997; 20 (9): 1462-1465
To compare the binding to cultured endothelial cells of mononuclear cells isolated from healthy volunteers and patients with NIDDM.Mononuclear cells were isolated from healthy volunteers (n = 11) and patients with NIDDM (n = 14) and incubated with ECV 304 cells, a human umbilical endothelial cell-derived transformed cell line. Following a period of incubation, the adherence of mononuclear cells to endothelial cells was determined.Adherence of mononuclear cells from patients with NIDDM was significantly greater (P < 0.05) than that of cells isolated from the healthy volunteers, and this difference persisted when adjusted for age, sex, and degree of obesity. Mononuclear cell binding to ECV 304 cells correlated significantly with fasting plasma glucose (r = 0.52, P < 0.01), insulin (r = 0.51, P < 0.01), triglyceride (r = 0.54, P < 0.01), and VLDL (r = 0.54, P < 0.01) and HDL cholesterol (r = -0.45, P < 0.05) levels, but not with either total or LDL cholesterol levels or blood pressure.Since the adherence of mononuclear cells to the endothelium represents the earliest step in atherogenesis, the observation that mononuclear cells from patients with NIDDM bind more avidly to cultured endothelial cells may help explain why accelerated atherosclerosis occurs in patients with NIDDM. The metabolic abnormality, or abnormalities, present in patients with NIDDM that is responsible for the enhanced adhesiveness of mononuclear cells requires further examination.
View details for Web of Science ID A1997XT09100023
View details for PubMedID 9283798
One-step HPLC purification procedure for porcine brain 90-kDa heat shock protein
PROTEIN EXPRESSION AND PURIFICATION
1997; 10 (2): 180-184
The 90-kDa heat shock protein (HSP90) was purified from porcine brain by a novel single-step purification procedure using diethylaminoethyl high-performance liquid chromatography (HPLC). About 4.8 mg of HSP90 was isolated from 25 g wet wt porcine brain tissue. The purified protein possessed a single moiety on one- and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining. Western blotting using monoclonal antibody prepared against human HSP90 confirmed its identity as HSP90. These results indicate that small-scale HPLC purification of HSP90 from porcine brain tissue can be readily accomplished, with high yield, using a convenient one-step purification method. The procedure described in this paper represents a significant improvement in current purification methods for the isolation of HSP90 from porcine brain.
View details for Web of Science ID A1997XH85600003
View details for PubMedID 9226713
MICROTUBULE MOVEMENT BY A BIOTINATED KINESIN BOUND TO A STREPTAVIDIN-COATED SURFACE
JOURNAL OF BIOLOGICAL CHEMISTRY
1994; 269 (11): 8610-8615
Kinesin, an ATP-dependent microtubule motor, can be studied in vitro in motility assays where the kinesin is nonspecifically adsorbed to a surface. However, adsorption can inactivate kinesin and may alter its reaction kinetics. We therefore prepared a biotinated kinesin derivative, K612-BIO, and characterized its activity in solution and when bound to streptavidin-coated surfaces. K612-BIO consists of the N-terminal 612 amino acids of the Drosophila kinesin alpha subunit linked to the 87-amino acid C-terminal domain of the biotin carboxyl carrier protein subunit of Escherichia coli acetyl-CoA carboxylase. The C-terminal domain directs the efficient post-translational biotination of the protein. We expressed K612-BIO at high levels using the baculovirus expression vector system and purified it to near-homogeneity. The expressed protein is completely soluble, and > 90% is bound by streptavidin. K612-BIO steady-state ATPase kinetics (KM,ATP = 24 microM, K0.5, microtubule = 0.61 mg ml-1, Vmax = approximately 25 s-1 head-1, 25 degrees C) are similar to those reported for intact kinesin. ATPase kinetics are not affected by the addition of streptavidin. Enzyme bound to a surface coated with streptavidin drove microtubule gliding in the presence of 2 mM ATP at 750 +/- 130 nm s-1 (26 degrees C). Activity was abolished by pretreatment of the surface with biotin, indicating that the microtubule movements are due to specifically bound enzyme. Motility assays based on specific attachment of biotinated enzyme to streptavidin-coated surfaces will be useful for quantitative analysis of kinesin motility and may provide a way to detect activity in kinesin derivatives or kinesin-like proteins that have not yet been shown to move microtubules.
View details for Web of Science ID A1994NB40900116
View details for PubMedID 8132586