JCBFM, July 2008.
You
can find all the JCBFM summaries in web format at:
All
articles are listed. My Immediate Relevance assessment is entirely implicit and
is designated with regard to work we are doing or contemplating RIGHT NOW. The Immediate
Relevance of an article might change in the future. Those papers with Immediate
Relevance rated VERY LOW do not get a Sullysummary.
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*1. Acute
functional recovery of cerebral blood flow after forebrain ischemia in rat.
Chao
Zhou, et al.
Sullysummary: Long story short:
these guys stroked rats, then tweaked their whiskers
and looked at relative cerebral blood flow (rCBF) in the somatosensory cortex
to evaluate circulatory recovery. Basically a technical paper, its real focus
is on describing improvements in laser blood flow measurements; a technique
called laser speckle imaging, augmented by statistical parametric mapping. It
might mean more to me if I had a firmer grasp of what "relative cerebral
blood flow" (not regional CBF) actually means, but since the authors of
this paper (and many others) don't actually tell me, I guess I'll have to wait
until one of y'all enlightens me. As near as I can tell, in this case it's the
ratio of the regional cerebral blood flow to the baseline blood flow. In any
event, the authors used their technique to reproducibly demonstrate that drCBF
magnitude doesn't change in response to whisker-tweakage, but the max drCBF is
delayed after ischemia. Whoa. Dude. That could mean
something.
Immediate
Relevance: Low-Medium.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200821a.pdf
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*2. Additive
effects of statin and dipyridamole on cerebral blood flow and stroke
protection. Hyung-Hwan Kim, et al.
Sullysummary: This is a
manufacturer-supported study of a combination therapy consisting of statin
(simvastatin) and dipyridamol (aka Persantine) in focal ischemic stroke, and is
of considerable interest because of its approach to development of a bimodal
combination therapy. Dipyrimadol (DP) is familiar to clinicians who send
patients for a "Persantine-Thall" examination, in which a patient
receives a radionuclide (Th-201) to assess the ischemic/infarcted area of the
myocardium. DP (Persantine) is given to "open up" the coronaries and
insure maximal penetration of the thallium. It is a vasodilator, working at
least in part through a phosphodiesterase inhibitory mechanism. It is also known
to be a platelet blocker (by the same mechanism), but the authors hypothesize
that its recently observed stroke protective effects are not solely
attributable to its platelet blocking properties. Here, they show (a) that
pretreatment with statin and DP, given individually, obey Krause's law,
limiting stroke volume in a dose-dependent fashion, (b) that
the combination of these two agents _at subtherapeutic levels_ works better
than either agent alone at reducing stroke volume, endothelium-dependent aortic
wall tension, neurodeficit, and (c) increase aortic cGMP levels. They
also show that (d) all of these effects are absent in eNOS-/- mice pretreated
in the same way. They conclude, reasonably enough, that statin and DP exert
additive NO-dependent vascular effects and suggest that the combination of
statin and DP has greater benefits in stroke protection than statin alone
through vascular protection. The major things that jumped out at me on first
read were (a) the applicability of their overall approach to combination
therapy development and (b) the curious discrepancy between figures 1 and 2
(I'll leave it to you to detect it, if you care to.) Of
interest primarily for methodological reasons.
Immediate
Relevance: HIGH.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200824a.pdf
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*3. Brief exposure to
hyperoxia depletes the glial progenitor pool and impairs functional recovery
after hypoxic-ischemic brain injury. Joshua D Koch1, et al.
Immediate
Relevance: VERY LOW.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200815a.pdf
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*4. Arctic ground
squirrel (Spermophilus parryii) hippocampal neurons tolerate prolonged
oxygen–glucose deprivation and maintain baseline ERK1/2 and JNK activation
despite drastic ATP loss. Sherri L Christian, et al.
Sullysummary: We buy our rodents
from Harlan. These guys have to go out on the glacier and _trap_ their rodents.
Remember THAT the next time you want to whine about something. Arctic ground
squirrels (AGS) are a hibernating species whose neurons are very resistant to
global ischemia and OGD. Here, the authors describe a hippocampal slice method
that has low baseline cell death, and use this model to investigate energy
metabolism and MAPK signaling in the AGS. I thought this paper might have
tangential Immediate Relevance to the work we will be doing for Karin.
Surprisingly, the authors found that, although these animals maintain Erk1/2
and JNK kinase activity longer, their resistence to OGD does not depend on MAPK
signaling or preservation of energy charge. The authors speculate that in this
model, prolonged Erk and JNK phosphorylation is a biomarker for overall
metabolic homeostatic maintenance. Interesting, but I'm not entirely sure the
long read was worth the candle.
Immediate
Relevance: Low-Medium.
Link
(PDF):http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200820a.pdf
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*5. Gene expression in
peripheral blood differs after cardioembolic compared with large-vessel
atherosclerotic stroke: biomarkers for the etiology of ischemic stroke. Huichun Xu, et al.
Sullysummary: I lost patience with
this one real quick. The authors tried to define gene expression profiles
in blood that differentiate cardioembolic from
large-vessel atherosclerotic stroke. Here's how it worked: as part of a larger
study, patients with acute ischemic stroke were screened and randomized to
either normal dose rt-PA or a low-dose rt-PA regimen with a platelet inhibitor.
These patients had blood drawn for gene expression (mRNA) profiles, which were
compared to healthy controls. A total of 33 patients were enrolled. The authors
report that blood expression profiles in cardioembolic stroke
patients--primarily neutrophil expression of immune modulation genes--are
distinctive from those of large-vessel atherosclerotic stroke
patients--primarily platelet and monocyte expression of hemostasis-related
genes. Okay, that _might_ be interesting, except there's a lot we don't know.
The authors don't tell us how many stroke patients were screened to get those
33 patients. If the literature is any guide, these patients represented an
extremely small subset of all acute stroke patients. They don't give us any
information on the decision instruments used to refer patients to one of the
t-PA arms. They don't tell us how many patients in each group (large vessel vs
cardioembolic) got regular vs. lo-dose t-PA. We don't know anything about the
stroke severity or outcome. All we know is that these are the gene profiles
they found in the (presumably small) subset of patients with acute ischemic
stroke who were (somehow) referred to the thrombolysis arms of their study, who
they SAY broke down into 21 large-vessel strokes and 12 cardioembolic strokes
(no data presented to affirm this) and whose presentation severity and outcomes
are completely unknown to us. Finally--and this is the real kicker--we don't
know what the gene profiles of these patients looked like right BEFORE they
stroked, and we don't know how gene profiles correlated, if at all, with
hemorrhage rate after thrombolysis. In short, what we DONT know about this
study, combined with its small numbers and highly restricted and restrictive
sampling method, makes its findings and conclusions
just about useless. At best, the data presented here could be used for
hypothesis generation. This is barely science.
Immediate
Relevance: Low.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200822a.pdf
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*6. Preconditioning
mediated by sublethal oxygen–glucose deprivation-induced cyclooxygenase-2
expression via the signal transducers and activators of transcription 3 phosphorylation. Eun J Kim et al.
Sullysummary: I think the first
thing that needs to be said is that Dr. Kim and his colleagues need to attend a
title-writing seminar. This is an excellent example of why our affiliation with
Karin is likely to be such a good idea. Here the authors proceed from
observations showeing that STATs are essential for cardioprotection by
precondition, and carry that work over to neuroprotection. In the heart, PC
causes serine phosphorylation of STAT1 and STAT3 via the ePKC à Raf-1 à MEK-1/2 à ERK1/2 signaling cascade, which in turn
bumps up COX-2 expression. This results in an increase of AA àPG H2 which, one supposes, must be a good
thing, if only because is uses up some arachidonate.
Using
a neuronal/astrocyte OGD model, the authors demonstrate that (1)
"preconditioning" OGD induces serine and tyrosine phosphorylation of
STAT3 (but not STAT1); (2) ePKC activation is involved in phosphorylation of
STAT3 after precondition (using a ePKC inhibitor); (3) ERK 1/2 activation is a
prerequisite to STAT3 serine phosph'n; (4) ERK-1/2 and ePKC do not co-IP with
STAT3 after preconditioning, indicating that other kinases are responsible for
PC-mediated STAT3 phosphorylation; and (5) inhibition of STAT3 activation
reduces both COX-3 expression and "neuroprotection."
The
"neuroprotection" thing bugs me: the authors use LDH assay in mixed
neuronal/astrocytic cultures. How much LDH came out of neurons and how much
from astrocytes. Rita? I confess my ignorance.
Overall, however, this study offers some evidence that, in the brain, PC
might
activate the sequence: ePKCàà ERK1/2 à (kinase?) à STAT3(P) à COX-2à
AA to PGH2 à creamy goodness. The
authors speculate, based on thin evidence, that the Mystery Kinase might be
p70S6, which obviously got my wheels turning. Overall, I have to say I'd be a
lot more excited about this paper if it had an in vivo arm. Still,
something we should have under our belt for our work with Karin.
Immediate
Relevance: Med-HIGH.
Link
(PDF):http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200826a.pdf
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*7. Incensole acetate: a
novel neuroprotective agent isolated from Boswellia
carterii. Arieh
Moussaieff,et al.
Sullysummary: Tree bark follows
Krause's Law.
Immediate
Relevance: Low.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200828a.pdf
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*8. Role
of cortical spreading depressions for secondary brain damage after traumatic
brain injury in mice. Louisa von Baumgarten, et al.
Immediate
Relevance: VERY LOW.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200830a.pdf
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*9. Neural progenitor
cells treated with EPO induce angiogenesis through the production of VEGF. Lei Wang, Michael Chopp, et al.
Sullysummary: Mike Chopp is just a
monster. He just cranks 'em out. This paper is strictly _in vitro_, though,
without any in situ tissue correlation. Similar to Mike's last paper, they used
a coculture system of mouse brain endothelial cells (MBECs) and neural
progenitor cells to investigate the hypothesis that neural progenitor cells
treated with rhEPO promote angiogenesis. Neural progenitor cells with rhEPO
secreted vascular endothelial growth factor (VEGF) and turned on the PI3K/Akt
system and ERK 1/2. Treatment also made MEBCs form cute little tubes. Whatever that means.
Immediate
Relevance: Low.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200832a.pdf
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*10. Hypoxia and
hypotension transform the blood flow response to cortical spreading depression
from hyperemia into hypoperfusion in the rat. Inna Sukhotinsky, et al.
Sullysummary: Primarily of interest
to us for the following reason: here's a paper looking at blood flow changes in
reperfusion, published in JCBFM, that didn't go anywhere near an MRI machine. Anthony,
isn't that interesting? Also some good tips in there for us vis-a-vis use of
Laser Doppler.
Immediate
Relevance: Medium.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200835a.pdf
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*11. Metabolic
origin of BOLD signal fluctuations in the absence of stimuli. Masaki
Fukunaga1, et al.
Immediate
Relevance: VERY LOW.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200825a.pdf
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*12. Use of acute hyperphenylalaninemia
in rhesus monkeys to examine sensitivity and stability of the L-[1-11C]leucine
method for measurement of regional rates of cerebral protein synthesis with
PET.
Carolyn B Smith, et al.
Immediate
Relevance: VERY LOW.
Link
(PDF): http://www.nature.com/jcbfm/journal/v28/n7/pdf/jcbfm200827a.pdf
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END SUMMARY.