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Q: Spinal Cord Injury(Immediate Therapy) ( Answered,   0 Comments )
Subject: Spinal Cord Injury(Immediate Therapy)
Category: Science > Biology
Asked by: greatone100-ga
List Price: $2.00
Posted: 26 Nov 2002 13:08 PST
Expires: 26 Dec 2002 13:08 PST
Question ID: 115033
Hypertonic Saline is postulated to improve outcome of spinal cord
inury by which of the following mechanisms (there can be more than
a. Inhibition of Lipid Peroxidation
b. Improved Reversal of Intracellular C++
c. Inhibition of Arachidonic Release
d. Increases Leukocyte Rolling And Adhesion
e. glucocorticoid activity
f. increased Na++ levels
g. reduces vascular resistance
h. all of the above
i. none of the above
Subject: Re: Spinal Cord Injury(Immediate Therapy)
Answered By: kutsavi-ga on 02 Dec 2002 14:25 PST
Hey there greatone, 

For the fee of $2.00, I could find the following on the uses of
hypertonic saline in traumatic brain/spinal cord injury.  I have a
medical background and as I presume you are a medical student, the
terminology used in the studies will undoubtedly be of help, adressing
as they do each of the multiple choice questions in your question. 
Each are also referenced to specific articles.

These sound like "take home test" questions that require research
beyond that which $2.00 is able to supply.  Each, however, addresses
the uses of hypertonic saline solution, at 7.5%, as opposed to NSL, on
specific neurological injuries.  If I can provide any further help,
please let me know:

Hypertonic saline (7.5% NaCl) increases osmosis and promotes movement
of endogenous fluid from the extravascular to the intravascular space.
It increases the inotropic function of the heart. It causes
constriction of the capacitance vessels, decreases resistance vessels
and causes dilatation of precapillary sphincters. The adverse effect
is hypokalemia. It has benefit in patients with closed-head injuries
or at risk of cerebral edema. Dextrose containing fluids should not be
used for volume expansion.

SHAHIN GHADIR, MS III Universidad Central del Caribe, School of
Medicine Department of Pediatrics Guest Editor Pediatric Bulletin

Enhancement of Drug Delivery by Hypertonic Saline Solution Following
Spinal Cord Injury
William F. Young, MD

We are in the final stages of completion.

Findings or Conclusions to Date:
Hypertonic saline and methyl prednisolone treated animals had better
neurologic outcome than methyl prednisolone alone treated animals.

Gene Expression During Posterolateral Lumbar Spine Fusion: Effect of
Scott D. Boden, MD; Michael A. Morone, MD, PhD; George Martin, MD;
Greg Hari, PhD; Michele Racine
Emory Spine Center, Emory University School of Medicine. and Veterans
Affairs Medical Center, Atlanta,GA

Introduction: Posterolateral spine arthrodesis may result in failure
to achieve a solid bony union in up to 35% of patients. Recent studies
using a validated rabbit model have characterized the healing process
using quantitative histomorphometry. However, little is known from a
molecular biology perspective about expression of bone and
cartilage-related genes during this process. In addition, the role of
bone morphogenetic proteins is unclear. Using current molecular
biology techniques (RT/PCR) small quantities of tissue can be used to
study the expression of specific genes. The goals of this
investigation were: 1) To describe the temporal and spatial pattern of
bone and cartilage-related gene expression; 2) To correlate the gene
expression patterns with the histologic healing patters; and, 3) To
describe the effect of bone morphogenetic protein-2 (BMP-2) on gene
expression during spine fusion healing.

Materials and Methods: Part I: After approval by the IACUC, 20 adult
New Zealand white rabbits underwent L4-5 posterolateral
intertransverse process spine arthrodesis using autogeneous iliac
crest bone graft. Rabbits were euthanized at 2 days, 4 days, 1, 2, 3,
4, 5, 6 or 10 weeks following surgery. Part II: 14 adulta NZW rabbits
underwent arthrodesis using autogeneous iliaccrest bone that had been
soaked in 1/5 mg/ml rhBMP-2 solution (Genetics Institute, Cambridge,
MA). Rabbits were euthanized at the same time points as above. RNA
Extraction. Fusion masses were harvested and divided into thirds (two
transverse process outerzones and one central zone). Each third was
then frozen in liquid nitrogen. Total RNA was extracted using 4 M
guanidine isothiocyanate. RNA was extracted from iliac crests
harvested from 4 animals to serve as a control for baseline gene
expression at time 0 in the fusion mass. The RNA then underwent
reverse transcription/polymerase chain reaction (RT/PCR) to study the
expression of various genes. Unique PCR primers were designed using
dequence information available in Genebank. The number of PCR cycles
was 22 for bone morphogenetic protein-2 (BMP-2), BMP-4, BMP-6, Type I
collagen, Type II collagen, osteopontin, osteonection, osteocalcin,
alkaline phosphatase and GAPDH (a housekeeping gene). All PCR products
were separated on a 12% acrylamide gel and exposed on a
phosphorimager. The intensities were normalized to that of GAPDH and
then normalized to the relative intensity of each mRNA PCR product at
time zero. Quantitation was performed on 2-3 PCR replicates of three
independent samples from separate RT reactions and expressed as mean +
standard error of the mean (SEM). A one-way analysis of variance
(ANOVA), with Bonferroni's post hoc multiple comparison test, was used
to detect differences at different time points. All finding described
below reached statistical significance defined as p<.05.

Results: Part I: A unique temporal and spatial pattern of
osteoblast-related gene expression was observed based on RT/PCR
analysis of RNA from the different zones of the fusion mass. During
the second and third weeks a significant increase was seen in Type I
collagen gene expression. Osteopontin (OP) and osteonectin (ON) were
both increased by 1 week, with osteopontin peaking in week 3 (150-fold
increase) and osteonectin in week 2 (175-fold increase). A 28-fold
increase in osteocalcin PCR product expression was seen in weeks 3-4
in the outer zones. Gene expression in the central zone of the fusion
mass lagged 1- 2 weeks behind that of the two outer zones corrieating
with the central lag effect previously observed in the histologic
healing sequence. Expression of several BMPs was also studied. In the
outer zones, increased BMP-2 expression was seen in weeks 2-6 with
peak expression in weeks 3-4 (40-fold increase). BMP-4 demonstrated a
different pattern with a 40-fold increase in week 1 that decreased
significantly by week 3. BMP-6 had an early increase on day 2
(54-fold) and a second peak (100-fold) in weeks 4-5. These findings
suggest unique time patterns of expression and possibly unique roles
for various BMPs during spine fusion.

Part II: Soaking the autogenous bone graft with rhBMP-2 had a dramatic
impact on the gene expression during spine fusion healing. Most
notably, there was a significantly greater increase in BMP-6
expression on day 2 (95-fold) in the outer zone and an earlier second
BMP-6 peak in the central zone at week 2 (instead of week 4). In
addition, expression of other bone-related genes described in Part I
was seen earlier and at higher levels in the presence of rhBMP-2. The
previously observed lag effect in the central zone was minimized with
the addition of rhBMP-2 that may explain the decreased nonunion rate
described in previous animal studies of spine fusion using rhBMP-2.

Discussion: We have shown that it is possible to reproducibly measure
gene expression in spine fusion masses using RT/PCR technology. BMP-6
was the earliest of the BMPs to show increased expression and may be a
critical factor in the initiation of spine fusion healing. Soaking of
autograft with rhBMP-2 increased the early BMP-6 peak and decreased
the central lag effect that may explain why fusions with rhBMP-2 heal
faster with less nonunions. In addition to helping understand how
rhBMP-2 may function in vivo, these baseline gene expression data will
facilitate the design of experiments with fusions enhanced
(ultrasound, electrical stimulation) or retarded (nicotine, NSAIDs) to
elucidate the potential mechanisms of action of these agents and to
design gene-specific biologic strategies to more effectively
manipulate the spine fusion healing process.

Platelet/Leukocyte Interactions Are Increased In Hemorrhagic Shock And
Attenuated By Hypertonic Saline Resuscitation (HTS)

K. Bradley NLD., R. Milner BS, R. Class PhD, C-Fisher B.S., R.
DeLaCadena NLD., &Buckman, 1VLD.*, A. Goldberg NLD., A. Pathak, IVLD.
and NL Badellino NLD.*

Temple University Philadelphia, PA 19140

Hemorrhagic shock has been shown to produce both platelet and
leukocyte activation. HTS resuscitation has been shown to attenuate
leukocyte activation. The effect of HTS resuscitation on platelet/
leukocyte interactions is less clear. This study examined whether
platelet/leukocyte conjugates occur in shock and whether HTS alters
these interactions.

Methods: Male Sprague-Dawley rats hemorrhaged to MAP=40mmHg for 1 hour
were resuscitated with HTS (1/4 shed volume). Whole blood sampled at
basal, 60 minutes shock and 15 minutes post-resuscitation was analyzed
by flow cytometry for platelet GPV and leukocyte CD45 markers and
expressed as % total events double positive for platelet/ leukocyte
conjugates. GPV and CD45 double positive cells were gated for size,
granularity and expression of CD11b and HIS48 granulocyte markers and
expressed as % gated events for platelet/granulocyte conjugates.

Results: Following hemorrhage, a significant increase in total
platelet/ leukocyte conjugates occurs. These interactions are
attenuated by HTS resuscitation. A significantly increased subset of
these cells are platelet/granulocyte conjugates that are also reduced
after HTS resuscitation.

Basal (n=6)
60' Shock (n=6)
Post (w=6)
P value**

total events
P <0.001

gated events
P = 0.00

Conclusion: Significant platelet/leukocyte conjugation occurs during
hemorrhage, Platelet/granulocyte conjugates represent a significant
subset of this population. HTS resuscitation reduced the number of
total platelet/leukocyte and platelet/granulocyte conjugates. This
decreased platelet/leukocyte interaction may provide a method by which
HTS prevents leukocyte activation following hemorrhage. Further, these
data may account for the improved microcirculatory flow observed
following HTS resuscitation.

Kevin M Bradley, XD.
Temple University Dept of Surgery
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