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. Mechanisms of anoxia tolerance in freshwater turtles
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
So, 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.
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 and carbon dioxide CO2 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 smaples 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.
Ok, 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.
Interested?
To join our network, simply email Mike Lee (leemt@anesthesia.ucsf.edu) in the Deptartment of Anesthesia.
When emailing, do let us know if you're interested in either or both of the studies. If so, we'll likely see you soon.
Bickler, P.E, Fahlman, CS, Taylor DM. Hypoxia-induced silencing of NMDA receptors in neonatal neurons: relationship to channel subunit composition and survival during anoxia. Neuroscience118:25-35, 2003.
Fahlman, C.S., Bickler, P.E., Sullivan, B, Gregory, G.A. Activation of the neuroprotective ERK signaling pathway by fructose-1,6-bisphosphate during hypoxia involves intracellular Ca2+ and phospholipase C. Brain Research 958: 43-51, 2002.
Bickler, PE, Warner, DS, Stratmann, G, Schuyler, J. GABA receptors contribute to isoflurane neuroprotection in organotypic hippocampal cultures. Anesthesia and Analgesia, 97: 564-71, 2003
Bickler, P.E., Fahlman, C.S., Ferriero, D.M. Hypoxia increases calcium flux through cortical neuron glutamate receptors via protein kinase C. J. Neurochemistry 88:878-84, 2004
O'Connor, T, Dubowitz G, Bickler, P. Pulse oximetry in the diagnosis of acute mountain sickness. High Altitude Biology and Medicine, 5: 341-8, 2004
Bickler, PE, Fahlman, C. Moderate increases in intracellular calcium activate neuroproective signals in hippocampal neurons. Neuroscience, 127:673-83, 2004
Feiner, JR, Bickler, PE, Estrada, S, Donohoe, PH, Fahlman, CS,, Schuyler, JA. Mild hypothermia, but not propofol, is neuroprotective in organotypic hippocampal cultures. Anesthesia and Analgesia, 100:215-25, 2005
Gray, J, Bickler, PE, Fahlman CS, Zhan X, Schuyler J. Isoflurane neuroprotection in hippocampal slice cultures requires intracellular Ca2+ and mitogen-activated protein kinases. Anesthesiology, 102: 606-15, 2005.
Hedrick,M, , Fahlman, C.S.Bickler, P. Intracellular calcium and survival of tadpole forebrain cells in anoxia. Journal of Experimental Biology, 208: 681-6, 2005.
Liu, C, Schuyler, JA, Cotton, JF, Fahlman CS, Au, J, Yost CS, Bickler, PE. Protective effects of TASK-3 (KCNK9) and related 2P K channels during cellular stress. Brain Research, 1031: 164-73, 2005.
Bickler, P.E., Feiner, J.R. and Severinghaus, J.W. Effects of skin pigmentation on pulse oximeter accuracy at low saturation. Anesthesiology, 102: 715-9, 2005.
Bickler, P., Zhan X., Fahlman C, Schuyler J. Isoflurane preconditions hippocampal neurons against oxygen/glucose deprivation: role of intracellular Ca2+ and MAP kinase signaling. Anesthesiology, In Press, 2005.
Fahlman CS, Bickler PE. The inhalation anesthetic isoflurane enhances Ca2+-dependent survival signaling in cortical neurons: modulation of MAP kinases, apoptosis proteins and transcription factors during hypoxia. Submitted, 2005
Dr. Philip E. Bickler
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.
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
