Bickler Lab UCSF - Research

Research

Philip Bickler's Research Interests Our laboratory is involved in a broad array of studies related to how the brain adapts to an insufficient supply of oxygen. The following are currently active research projects:

1. Improving the hypothermia and hypoxia tolerance of neurons to benefit neuroprotection
2. The role of Neurogenesis in the young and old brain in mediating cognitive outcome following anesthesia
3. Developmental changes in the tolerance of hypoxia in rodents
4. Preconditioning mechanisms
5. Adaptation of humans to high altitude environments
6. Anoxia tolerance in marine mammal neurons
7. Hypothermia and ion channel modulation in cold and hypoxia tolerant neurons


1. Mechanisms of anoxia tolerance in freshwater turtles (Pseudemys and Trachemys), focusing on the regulation of ionic conductances (glutamate receptors, sodium channels) that modulate cellular energy consumption and survival. The use of intracellular calcium as a signaling molecule in anoxia tolerance is also a focus of study.

 


2. General anesthesia is associated with a high incidence of cognitive decline in elderly patients. Recent data suggest that the brain can generate new neurons from neural stem cells (neurogenesis). Neurogenesis is important in maintaining cognitive function. Augmentation of neurogenesis causes cognitive improvement and reduction of neurogenesis causes cognitive decline. Cognitive dysfunction following anesthesia has been demonstrated in aging rats. However, in young rats isoflurane improves cognitive function. Our preliminary data show that isoflurane causes increased neurogenesis in young rats. We hypothesize that anesthesia increases cognitive function in young rats by increasing neurogenesis and that anesthesia decreases neurogenesis in old rats causing cognitive decline. To test this hypothesis we will first evaluate neurogenesis following isoflurane or propofol anesthesia in young and old rats by immunocytochemical techniques including BrdU (marker of dividing cells) labeling of neural stem cells in the dentate gyrus of the hippocampus. Second we will assess electrophysiologic function of the synaptic network in hippocampal slices by measuring long term potentiation, the electrophysiologic correlate of learning and memory. Third we will assess neurobehavioral function in vivo.

 


3. Developmental changes in the tolerance of hypoxia in rodents, specifically how signaling mechanisms related to changing oxygen levels are signals for development and regulation of ionic conductances.

 


4. Preconditioning mechanisms involved in hypoxic and anesthetic preconditioning. The main hypotheses being tested focus on how changes in intracellular calcium result in neuroprotective changes in signaling pathways, survival proteins and gene expression.

 


5. Adaptation of humans to high altitude environments, especially cardiorespiratory changes during acclimatization

 


6. Anoxia tolerance in marine mammal neurons

 


7. Hypothermia and ion channel modulation in cold and hypoxia tolerant neurons

 

Pulse-Oximetry and Methemoglobin Studies

Pulse  oximeter studies :: Bickler Lab

What is the Pulse-Ox network?


It's a large group of study-volunteers that participate in studies with our lab. Volunteers in our network routinely come back several times. The studies are generally pretty easy, pay well, and we try to have a good time.

If you want to join, read these bits of info and simply sign up below.

We pay you, you help advance the accuracy of non-invasive detectors, and we provide cookies and music during the studies.

Every couple of weeks or so, we announce new study dates. Volunteers registered with our network get notice of these dates, and first-come first served emails are allocated spots for the study days.

We generally run studies every other week, on Wednesdays and Thursdays.

Bickler Lab Pulse Oximeter studies

What is a pulse oximeter anyway?


It's pictured above, and it's a non-invasive device that uses light to measure various physiologic variables. They've been around for 20 years, and principally they're used to easily measure the amount of oxygen O2 saturation in your blood.

What is involved in the study?


This study pays $75-$100, and involves a little over an hour of your time. This study involves multiple breathing tests with brief, safe low levels of oxygen and withdrawal of 20-25 small blood samples (about 1.0 ml each). We withdraw these small samples via a wrist arterial catheter, which is inserted by the anesthesiologist under local anesthesia (lidocaine to numb the area). Total blood drawn during the study is about an ounce, or about 1/10th the blood you give when you donate.

What determines eligibility?


To participate, you must be a healthy non-smoker in good shape, between 18 to 50 years of age, without asthma, high or abnormally low blood pressure, diabetes, heart disease, lung disease, or obesity.

Pulse oximeterOk, but what is the methemoglobin study?


These are pretty cool, in fact. Here's why:

Methemoglobin is a cousin of hemoglobin, the protein in your blood that carries oxygen. Normally, hemoglobin's iron molecules are in the 2+ oxidation state: Fe2+. In this state, they carry oxygen. When another electron is knocked off, iron is further oxidized in the 3+ state: Fe3+.

This new state is what is called methemoglobin. It can no longer shuttle oxygen to your tissues. This is typicaly measured invasively, which is harder on the patient in addition to be a relatively slow method of detection. Not for long, though.....

Manufacturers are developing non-invasive devices similar to pulse-oximeters to detect the presence of methemoglobin. And it's all done quickly, without the need for needles. While these devices are being developed and tested, you can play a part in advancing the accuracy of these important devices.

What's involved?


This study would require around 2 to 2.5 hours of your time, and it pays $200. To induce the formation of met-Hb in our study, a slow infusion of sodium nitrite is given via an intravenous line. Sodium nitrite oxidizes normal hemoglobin and produces methemoglobin. The nitrite infusion will slowly increase met-Hb in the blood from a normal level of .1%-1% to about 11%-13%. Levels of methemoglobin above this (above 20%) may cause fatigue, headache, exercise intolerance, dizziness, and mental status changes. Our study is not interested in these high levels, and at our levels we generally find volunteers report no observable changes.

Blood samples will be periodically drawn from an arterial line and analyzed in a co-oximeter, much like our usual pulse-ox studies. Upon initial infusion of the nitrite, your body already begins to metabolize methemoglobin back to normal hemoglobin. Once the study is complete, it will take around 2-4 hours for methemoglobin to drop to pre-study levels, so strenuous exercise immediately after the study is discouraged for a few hours.

So what is Carboxyhemoglobin?


Carboxyhemoglobin is a complex formed by the binding of carbon monoxide and hemoglobin. This complex is formed in the human body when cabrbon monoxide is inhaled, most commonly from tobacco smoke. The formation of this complex can hinder the delivery of oxygen to your tissues.

What's involved?


This study would require around 2 to 2.5 hours of your time, and it pays $200. In our study, you will be given a very small, safe dose of carbon monoxide to inhale which will increase your carboxyhemoglobin levels to around 13%, approximately equivalent to smoking a pack of cigarettes. Some possible side effects include fatigue, or a feeling of light headedness. We will have pure oxygen on hand to reverse the effects if you feel any of those symptoms..

Throughout the study, we will periodically take 1cc sized blood samples from an arterial line which we will analyze in a co-oximeter machine. Those result will be compared with the results of a non-invasive oximeter, helping to determine it's accuracy. After the completion of the study, it will take between 4-6 hours for the carbon monoxide to leave your system so it is recommended that you not participate in any strenuous activity immediately after.

Interested?


To join our network, simply email Paul Au (aupaul@anesthesia.ucsf.edu) in the Deptartment of Anesthesia.

For more information on our studies, please visit www.hypoxialab.com.

Publications

Reversal of experimental paralysis in a human by intranasal neostigmine aerosol suggests a novel approach to the early treatment of neurotoxic envenomation.
Lewin MR, Bickler P, Heier T, Feiner J, Montauk L, Mensh B.
Clin Case Rep. 2013 Oct;1(1):7-15. doi: 10.1002/ccr3.3. Epub 2013 Jul 24.

Early Treatment with Intranasal Neostigmine Reduces Mortality in a Mouse Model of Naja naja (Indian Cobra) Envenomation.
Lewin MR, Samuel SP, Wexler DS, Bickler P, Vaiyapuri S, Mensh BD.
J Trop Med. 2014;2014:131835. doi: 10.1155/2014/131835. Epub 2014 May 14.

Limitations of Mild, Moderate, and Profound Hypothermia in Protecting Developing Hippocampal Neurons After Simulated Ischemia.
Gregersen M, Lee DH, Gabatto P, Bickler PE.
Ther Hypothermia Temp Manag. 2013 Dec 1;3(4):178-188.PM

Factors affecting the performance of 5 cerebral oximeters during hypoxia in healthy volunteers.
Bickler PE, Feiner JR, Rollins MD.
Anesth Analg. 2013 Oct;117(4):813-23. doi:

Accuracy of the Lifebox pulse oximeter during hypoxia in healthy volunteers.
Dubowitz G, Breyer K, Lipnick M, Sall JW, Feiner J, Ikeda K, MacLeod DB, Bickler PE.
Anaesthesia. 2013 Dec;68(12):1220-3. doi: 10.1111/anae.12382. Epub 2013 Aug 31.

Xenon neurotoxicity in rat hippocampal slice cultures is similar to isoflurane and sevoflurane.
Brosnan H, Bickler PE.
Anesthesiology. 2013 Aug;119(2):335-44. doi:

Accuracy of carboxyhemoglobin detection by pulse CO-oximetry during hypoxemia
Feiner JR, Rollins MD, Sall JW, Eilers H, Au P, Bickler PE.
Anesth Analg. 2013 Oct;117(4):847-58. doi:

Propofol at clinically relevant concentrations increases neuronal differentiation but is not toxic to hippocampal neural precursor cells in vitro.
Sall JW, Stratmann G, Leong J, Woodward E, Bickler PE.
Anesthesiology. 2012 Nov;117(5):1080-90. doi:

Anesthetic protection of neurons injured by hypothermia and rewarming: roles of intracellular Ca2+ and excitotoxicity.
Bickler PE, Warren DE, Clark JP, Gabatto P, Gregersen M, Brosnan H.
Anesthesiology. 2012 Aug;117(2):280-92.

Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats.
Shih J, May LD, Gonzalez HE, Lee EW, Alvi RS, Sall JW, Rau V, Bickler PE, Lalchandani GR, Yusupova M, Woodward E, Kang H, Wilk AJ, Carlston CM, Mendoza MV, Guggenheim JN, Schaefer M, Rowe AM, Stratmann G.
Anesthesiology. 2012 Mar;116(3):586-602. doi: 10.1097/ALN.0b013e318247564d.

The emergence level of the musculocutaneous nerve from the brachial plexus: implications for infraclavicular nerve blocks.
Pianezza A, Salces y Nedeo A, Chaynes P, Bickler PE, Minville V.
Anesth Analg. 2012 May;114(5):1131-3. doi: 10.1213/ANE.0b013e3182498643. Epub 2012 Feb 6.

Hypothermia and rewarming injury in hippocampal neurons involve intracellular Ca2+ and glutamate excitotoxicity.
Warren DE, Bickler PE, Clark JP, Gregersen M, Brosnan H, McKleroy W, Gabatto P.
Neuroscience. 2012 Apr 5;207:316-25. doi: 10.1016/j.neuroscience.2011.12.034. Epub 2012 Jan 12.

Hypoxic preconditioning failure in aging hippocampal neurons: impaired gene expression and rescue with intracellular calcium chelation.
Bickler PE, Fahlman CS, Gray JJ.
J Neurosci Res. 2010 Dec;88(16):3520-9. doi: 10.1002/jnr.22508. Epub 2010 Oct 8.

Improved accuracy of methemoglobin detection by pulse CO-oximetry during hypoxia.
Feiner JR, Bickler PE.
Anesth Analg. 2010 Nov;111(5):1160-7. doi: 10.1213/ANE.0b013e3181f46da8. Epub 2010 Sep 14.

Perioperative hypothermia (33 degrees C) does not increase the occurrence of cardiovascular events in patients undergoing cerebral aneurysm surgery: findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial.
Nguyen HP, Zaroff JG, Bayman EO, Gelb AW, Todd MM, Hindman BJ; IHAST-MIDS and IHAST Investigators.
Anesthesiology. 2010 Aug;113(2):327-42. doi: 10.1097/ALN.0b013e3181dfd4f7.

Enhanced hypoxic preconditioning by isoflurane: signaling gene expression and requirement of intracellular Ca2+ and inositol triphosphate receptors.
Bickler PE, Fahlman CS.
Brain Res. 2010 Jun 22;1340:86-95. doi: 10.1016/j.brainres.2010.04.059. Epub 2010 Apr 29.

Antifreeze protein suppresses spontaneous neural activity and protects neurons from hypothermia/re-warming injury.
Rubinsky L, Raichman N, Lavee J, Frenk H, Ben-Jacob E, Bickler PE.
Neurosci Res. 2010 Jul;67(3):256-9. doi: 10.1016/j.neures.2010.04.004. Epub 2010 Apr 14.

Erythropoietin promotes hippocampal neurogenesis in in vitro models of neonatal stroke.
Osredkar D, Sall JW, Bickler PE, Ferriero DM.
Neurobiol Dis. 2010 May;38(2):259-65. doi: 10.1016/j.nbd.2010.01.015. Epub 2010 Feb 1.

Isoflurane does not affect brain cell death, hippocampal neurogenesis, or long-term neurocognitive outcome in aged rats.
Stratmann G, Sall JW, Bell JS, Alvi RS, May Ld, Ku B, Dowlatshahi M, Dai R, Bickler PE, Russell I, Lee MT, Hrubos MW, Chiu C.
Anesthesiology. 2010 Feb;112(2):305-15. doi: 10.1097/ALN.0b013e3181ca33a1.

Accuracy of methemoglobin detection by pulse CO-oximetry during hypoxia.
Feiner JR, Bickler PE, Mannheimer PD.
Anesth Analg. 2010 Jul;111(1):143-8. doi: 10.1213/ANE.0b013e3181c91bb6. Epub 2009 Dec 10.

No association between intraoperative hypothermia or supplemental protective drug and neurologic outcomes in patients undergoing temporary clipping during cerebral aneurysm surgery: findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial.
Hindman BJ, Bayman EO, Pfisterer WK, Torner JC, Todd MM; IHAST Investigators.
Anesthesiology. 2010 Jan;112(1):86-101. doi: 10.1097/ALN.0b013e3181c5e28f.

Expression of signal transduction genes differs after hypoxic or isoflurane preconditioning of rat hippocampal slice cultures.
Bickler PE, Fahlman CS.
Anesthesiology. 2009 Aug;111(2):258-66.

Consensus statement: first international workshop on anesthetics and Alzheimer's disease.
Baranov D, Bickler PE, Crosby GJ, Culley DJ, Eckenhoff MF, Eckenhoff RG, Hogan KJ, Jevtovic-Todorovic V, Palotás A, Perouansky M, Planel E, Silverstein JH, Wei H, Whittington RA, Xie Z, Zuo Z.
Anesth Analg. 2009 May;108(5):1627-30.

Isoflurane inhibits growth but does not cause cell death in hippocampal neural precursor cells grown in culture.
Sall JW, Stratmann G, Leong J, McKleroy W, Mason D, Shenoy S, Pleasure SJ, Bickler PE.
Anesthesiology. 2009 Apr;110(4):826-33.

Inositol 1,4,5-triphosphate receptors and NAD(P)H mediate Ca(2+) signaling required for hypoxic preconditioning of hippocampal neurons.
Bickler PE, Fahlman CS, Gray J, McKleroy W.
Neuroscience. 2009 Apr 21;160(1):51-60. Epub 2009 Feb 13.

Effect of nitrous oxide use on long-term neurologic and neuropsychological outcome in patients who received temporary proximal artery occlusion during cerebral aneurysm clipping surgery.
Pasternak JJ, McGregor DG, Lanier WL, Schroeder DR, Rusy DA, Hindman B, Clarke W, Torner J, Todd MM; IHAST Investigators.
Anesthesiology. 2009 Mar;110(3):563-73.

Arctic ground squirrel (Spermophilus parryii) hippocampal neurons tolerate prolonged oxygen-glucose deprivation and maintain baseline ERK1/2 and JNK activation despite drastic ATP loss.
Christian SL, Ross AP, Zhao HW, Kristenson HJ, Zhan X, Rasley BT, Bickler PE, Drew KL.
J Cereb Blood Flow Metab. 2008 Jul;28(7):1307-19. Epub 2008 Apr 9.

Dark skin decreases the accuracy of pulse oximeters at low oxygen saturation: the effects of oximeter probe type and gender. Feiner JR, Severinghaus JW, Bickler PE.
Anesth Analg. 2007 Dec;105(6 Suppl):S18-23, tables of contents.

Hypoxia tolerance in reptiles, amphibians, and fishes: life with variable oxygen availability.
Bickler PE, Buck LT. Annu Rev Physiol. 2007;69:145-70. Review.

People

Dr. Philip E. BicklerPhilip E. Bickler, MD, PhD
Professor of Anesthesia

Dr. Philip E. Bickler received his Bachelors Degree in Biology at UC Riverside in 1977. He attended graduate school at UCLA, receiving a PhD in Biology in 1981. From there he went to Scripps Institution of Oceanography as an NSF and NIH postdoctoral fellow from 1981-1983 where he studied acid-base balance in hibernation. During Medical School at UCSD (1983-1986) he worked with Frank Powell in the Dept. of Medicine on Intrapulmonary Shunts in Duck Lungs and Alligators. In 1986 he moved to UCSF to work with John Severinghaus.  He went on to complete his Anesthesiology residency at UCSF and he has been a faculty member there since 1991.

He lives with his family of a wife, three children and one chocolate labrador in Larkspur, across the Golden Gate Bridge from San Francisco.

 


Paul AuPaul Au, BS
Clinical Research Coordinator

Paul joined the Bickler lab in the summer of 2009 as the coordinator of the pulse-oximetry study. He spent 3 years in his prior job, also in the department of anesthesia, working for Dr. Spencer Yost where he conducted experiments studying tandem pore potassium channels using voltage clamping in xenopus oocytes. Paul comes to the Bickler lab with a BS degree from UC Davis in Biological Sciences. When Paul is not in the lab, he can be found rock climbing and cooking, two of his biggest passions.


Pablo GabattoPablo Gabatto, BS
Staff Research Associate III/ Lab Manager

Pablo joined the Bickler group in March of 2009 but has been working at UCSF since
August of 2004. He brings years of experience from working in both the academic and
industry sectors of research. Pablo received his B.S. in Microbiology from UCSD. He
later travelled abroad studying in Lyon, France and then went on to teach English in
Budapest, Hungary. When he isn’t in the lab Pablo enjoys snowboarding and
backpacking in the mountains. You can also find him all over the city at numerous art
and music events.

 



Maribel PinedaMaribel Pineda, BS
Administrative Assistant

Maribel was born in Nicaragua but raised in San Francisco.  She joined the Bickler group in October 2008 and provides administrative support for the lab.  In addition to supporting Dr. Bickler’s lab, Maribel also supports six other anesthesia labs and has been working at UCSF since December 1999. She brings decades of experience of working in both the academic and private sectors of research, clinical, and financial areas.  
 
Maribel treasures her weekends and is a Big Fan of the warm weather and beaches and anything involved in most outdoor activities.  Dancing and music are up there, too!

 


Photos

 

Contact

Philip E. Bickler MD, PhD


Professor of Anesthesia
University of California at San Francisco
Sciences Building, Room S-257, Box 0542
513 Parnassus Ave.
San Francisco, CA 94143-0542

Phone: 415 476-1411
Fax: 415 476-8841
Email: bicklerp@anesthesia.ucsf.edu

For inquiries about conducting a pulse oximeter validation study, contact Paul Au.

Paul Au


Clinical Research Coordinator
Phone: 415-476-1412
Email: aupaul@anesthesia.ucsf.edu

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