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Osmotic pressure gradients and joint effusions.

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Osmotic Pressure Gradients and Joint Effusions
By RICKARD
L. LIPSON,EDWARD
J. BALDES,
JOSEPH
A. ANDERSON
AND HOWARD
F. POLLEY
This study reveals that in rheumatoid
joint disease the total osmotic pressure
of synovial fluid tends to be lower than,
or equal to, that of plasma. With local
articular or general systemic improvement the total osmotic pressures of synovial fluid and plasma tend to increase,
and that of synovial fluid may exceed
that of plasma. The colloid osmotic
pressure of synovial fluid from joints of
patients with rheumatoid arthritis was
lower than that of plasma.
L e presente studio revela que in morbos
rheumatic del articulationes le total
pression osmotic del liquido synovial
tende a esser inferior o equal a ill0 de
plasma. Con local melioration articular
o con melioration constitutional, le total
pressiones osmotic del liquidos synovial
e del plasma tende a montar, e ill0 del
liquido synovial pote exceder ill0 del
plasma. Le colloide pression osmotic de
liquido synovial a b articulationes de patientes con arthritis rheumatoide esseva
inferior a ill0 del plasma.
T
HE MECHANISMS RESPONSIBLE for the abnormal accumulation of
fluid in the joint space are complex and poorly understood. Increase in
the colloid osmotic pressure of the synovial fluid is usually cited as the principal factor in the formation and maintenance of joint eff~sions.l-~
However, the
colloid osmotic pressures of synovial fluid and plasma and the gradient between them appear to require further study before their role can be fully
understood.
In an attempt to clarify the role of the osmotic pressure of synovial fluid
and plasma and the resultant gradient” and its role in the pathophysiology of
joint effusions, a study was made of the colloid and total osmotic pressures
of fresh paired samples of human synovial fluid and plasma.
MATERIALAND METHODS
Samples of plasma and synovial fluid were obtained from 20 patients while they were
in the fasting state. Thirteen patients were classified according to the diagnostic criteria
of the American Rheumatism Association4 as having “definite” and two as having “possible” rheumatoid arthritis; two had rheumatoid spondylitis with rheumatoid involvement of the peripheral joints, and three patients had one or another of the following
conditions: Reiter’s syndrome, chondromalacia of the patella and metastatic carcinoma in
the lung (primary site unknown) without apparent articular involvement.
Venous blood was drawn into a 5-ml. syringe that had been rinsed with an aqueous
Read at the interim session of the American Rheumatism As.yociation, Boston, Massachu5 and 6, 1963.
This investigation was supportad in part b y Research Grant ASP-9880-C1 from the
National Institutes of Health, Public Health Service.
*The term “osmotic gradient” is suggested because “gradient” indicates a dynamic
system whereas “difference” in the terminology of physics implies a steady state and
the system being studied in this report is not a static one.
setts, December
29
ARTHRITIS AND RHEUMATISM,VOL. 8, No. 1 (FEBRUARY),
1985
30
LIPSON, BALDES, ANDERSON, POLLEY
solution of heparin sodium. The sample was centrifuged to separate the cells and plasma
within 1 hour after the specimen had been obtained, and the plasma was then drawn
into a 2-ml. syringe where it was kept until studies were done.
The synovial fluid was obtained by aspiration of one or both knee joints of each patient immediately after collection of the blood. The usual procedure for aspiration was
employed except that special care was taken to avoid the introduction of any local
anesthetic into the joint space. A sample of synovial fluid was first collected from each
joint in a 5-ml. syringe that had been rinsed with an aqueous solution of heparin SOdium and sent to the laboratory for determination of the osmotic pressure. Preliminary
studies demonstrated that the amount of heparin sodium used to rinse the syringes did
not alter the total osmotic pressure, and recently Losowsky, Alltree and Atkinson5 reported that heparin did not affect the plasma colloid osmotic pressure.
After the collection of the first specimen, the remainder of the synovial fluid was
removed from the joint for determination of the specific gravity (refractometer method)
and total protein content (biuret method). If steroids were to be given intra-articularly,
37.5 mg. of hydrocortisone acetate was instilled at this time.
Osnwtic Pressure Studies. The total osmotic pressure was determined on 36 fresh,
paired specimens from the 20 patients, and the colloid osmotic pressure was determined
on 14 paired specimens from 10 of the patients. Studies were repeated once in the course
of observation and therapy of six patients and a second time on two patients. Determinations also were repeated on several specimens that had been stored for weeks to months
in the refrigerator (5" C.) and on three of them after they had been frozen (-70" C.)
for 1 week.
The osmotic pressure studies were done within 24 hours after the samples were obtained except when studies were repeated weeks or months later to determine the effect
of storage or of freezing. If the initial determination was not done immediately, the
samples were stored under refrigeration in a sealed syringe during the short (not more
than 12 hours) delay.
The total osmotic pressure was measured by vapor pressure osmometer as described by
Baldes and Johnson.0 The osmometer was arranged so that two samples of the same
specimen could be evaluated simultaneously. The rcference solution used was 0.9 per
cent sodium chloride and the results are expressed in terms of per cent of sodium chloride. Double galvanometric deflections and repeated determinations with reversal of the
position of the drops of samples and reference solutions were used to increase the reliability of the determinations so that the accuracy attained was
,005 per cent NaCl.
The colloid osmotic pressure was measured by an osmometer patterned after the one
described by Reiff and Yiengst.7 A Statham P23De pressure transducer* was used as the
pressure sensing device, and the membrane was a Bac-T-Flex membrane filter no. B l 8 t
which has an average pore diameter of 10 to 20 millimicrons. The estimations were
performed at 37" C. with distilled water as the dialyzing fluid. The results were expressed
in millimeters of water.
Definition and Grading of Improvement. General systemic improvement was considered
present when there was a recognizable decrease in fever, fatigue and morning stiffness.
Local articular improvement was considered present when there was a decrease in at least
three of the four following criteria: (1) tenderness to palpation, ( 2 ) local heat, ( 3 ) synovial swelling, and ( 4 ) limitation of motion.
General articular improvement was indicated by local improvement of these criteria in
at least three fourths of the affected joints. Systemic or local articular improvement or
both were judged to be mild, moderate, marked or complete depending on the degree
to which the criteria were modified in comparison to the pre-aspiration status. Thus, an
*
*Statham Instruments, Inc., Los Angeles, California.
tschleicher & Schuell Co., Keene, New Hampshire.
31
OSMOTIC PRESSURE GRADIENTS
estimated 25 per cent reduction was considered mild improvement; 50 per cent reduction, moderate improvement; 75 per cent reduction, marked improvement; 100 per cent
reduction, complete remission.
RESULTS
The total osmotic pressure of synovial fluid from the 20 patients varied
from 0.816 to 0.896 per cent NaCl with a mean of 0.874 per cent NaCI, while
that of plasma ranged from 0.825 to 0.894 with a mean of 0.876. At the height
of the effusion the total osmotic pressure of the synovial fluid tended to be
less than, or equal to, that of the plasma; the difference was significant at p =
.01 ( t = 2.9356). However, in patients with rheumatoid arthritis with local
articular or general systemic improvement, the total osmotic pressures of both
synovial fluid and plasma were likely to increase, but the total osmotic pressure
of the synovial fluid tended to become greater than that of plasma (table 1).
This table shows the correlation of only certain findings but statistical analysis
revealed a significant difference in the total osmotic pressure of the synovial
fluid and plasma before treatment, as just cited. After treatment the total
osmotic pressure of both the synovial fluid and plasma was increased. In the
synovial fluid the pressure increased from a mean of 0.869 to 0.883 ( p < .001;
t = 8.1267). In the plasma the total osmotic pressure increased from 0.870 to
0.878 ( p < .01; t = 3.1319). After treatment, the total osmotic pressure of
synovial fluid was greater than that of plasma, the difference being significant
at p = 0.5 ( t = 2.3943).
The colloid osmotic pressure of synovial fluid was consistently less than the
colloid osmotic pressure of plasma. The pressure varied from 145 to 285 mm.
H 2 0 for rheumatoid synovial fluid with a mean value of 197 mm. and from
220 to 430 mm. for plasma, with a mean value of 328 mm. In one patient
without evident articular disease, the colloid osmotic pressures of the synovial
fluid and plasma were 62.5 mm. and 245 mm. HzO, respectively.
No correlation was evident between the colloid and total osmotic pressures
of either the plasma or synovial fluid in the 10 patients whose fluids were
available for determinations of colloid osmotic pressure. The rheumatoid arthritis in eight of these patients was classified as “definite,” and in one as
“possible,” and there was no essential difference in the data of the two
categories. Also, neither the total nor colloid osmotic pressure of the synovial
fluid showed a direct correlation with the total protein content or specific
gravity (table 2).
A comparison of the total osmotic pressures of synovial fluid from both
knees in four patients and the colloid osmotic pressures of fluids from one
patient revealed no significant difference between the fluids from both knees
in the same patient (table 3).
Storage of the specimens at 5” C. had a varied effect on the total osmotic
pressure but usually resulted in an increase. Freezing (-70” C.) the specimens had little effect on the total osmotic pressure but did reduce the colloid
osmotic pressure (table 4) which was associated with an apparent decrease
in viscosity.
32
LIPSON, BALDES, ANDERSON, POLLEY
Table 1.-Effect
Case
Specimen
from Knee’
Days after
Previous
Deterniination
of Improvement on Total Osmotic Pressure
in Rheumatoid Arthritis
Total Osmotic Pressure,
per cent NaCl
Synovial fluid Plasma
Comments : Hydrocortisone Acetate
Injection into Knee?; Local Art.cular Improvement$ Unless
Otherwise Stated
5
0.874
0.884
0.880
0.881
Hydrocortisone into L.
Marked improvement in L.
0
6
0
6
0.859
0.879
0.858
0.882
0.866
0.877
0.866
0.877
Hydrocortisone injected into L.
Moderate improvement in R.
Hydrocortisone into L.
Marked improvement in L.
0
60
0.872
0.886
0.871
0.893
No hydrocortisone
0
5
0.882
0.896
0.889
0.889
Hydrocortisone into L.
Marked improvement in L.
0
11
0.862
0.872
0.857
0.867
0
0.867
0.867
49
0.884
0.876
Hydrocortisone into R.
Mild improvement; hydrocortisone injected into R.
Hydrocortisone into L.; injection coincides with second
injection into R.
Marked general systemic and
articular improvement
0
6
0.864
0.878
0.877
0.879
0.889
0.862
0.875
0.872
0.875
0.872
0
5
0
5
Marked general systemic and
articular improvement
No hydrocortisone
Hydrocortisone into L.
Moderate improvement in R.
Hydrocortisone into L.
Marked improvement in L.
“L = left knee; R = right knee; specimens were from affected knees.
f37.5 Mg. of hydrocortisone acetate was injected in each instance indicated.
*Definitions of improvement are described in the text.
COMMENT
The total osmotic pressure of any solution depends on the number, and for
large molecules, the type of particles of solute per unit volume of solvent. An
isolated solution has no osmotic pressure, for in order to develop osmotic
pressure, the solution must be separated from either a pure solvent or a more
dilute solution by a semipermeable membrane. Plasma and interstitial fluid
have equal total osmotic pressures ( isosmotic) which are approximately 5100
mm. Hgs and almost entirely the result of the crystalloidal solutes. The capillary walls are freely permeable to the crystalloidal solutes which, therefore,
exert no osmotic force across the endothelium. The capillary, on the other
hand, is not as permeable to proteins as to crystalloids, therefore, the concentration of protein in the interstitial fluid differs from that in plasma. This
difference in concentration of protein exerts an osmotic effect known as the
“colloid osmotic pressure” which for the plasma, when compared with inter-
33
OSMOTIC PRESSURE GRADIENTS
Table 2.-Osmotic Pressure, Specific Gravity and Total Protein of
Synovial Fluid in 16 Patients
Osmotic Pressure
Case
1
3
7
8
9
10
11
12
13
14
15
16
17
18
19
Diagnosis
Volume
Aspirated,
ml.
Specific
Gravity
Total Protein,
Gm./100 ml.
Total,per
30
45
18
28
35
1.030
1.034
1.018
1.027
1.028
4.8
5.4
3.15
3.9
4.5
0.874
0.866
0.862
0.877
0.864
180
190
155
145
185
40
35
30+
40
3
1.025
1.029
1.031
1.025
1.015
3.35
4.87
5.1
3.35
1.6
0.816
0.866
0.862
0.816
0.893
155
255
285
155
62.5
20
10
10f
5
1.016
1.016
1.027
1.014
4.26
2.77
4.5
3.2
0.872
0.896
0.869
0.876
-
30+
1.031
6.8
0.867
-
Rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis*
Rheumatoid spondylitis
Rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis
Metastatic cancer in
lung, primary unknown, no joint
involvement
Rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis*
Chondromalacia
patellae
Rheumatoid spondylitis
Reiter’s syndrome
Colloid,
cent NaCl mm. HLO
-
-
1
0.882
*-Possible” rheumatoid arthritis; all other cases of rheumatoid arthritis referred to in
20
this table were classified as “definite.”
stitial fluid free of protein, is of the order of 25 to 30 mm. Hg.* Despite the
fact that the colloid osmotic pressure is such a small part of the total, it is
physiologically the most significant part. It is known as the “effective” osmotic
pressure because it is the osmotic force that actually moves fluid across the
capillary wall.
Articular effusion can be described as a form of localized edema in which
the excessive amount of fluid is retained in a relati\,ely large interstitial space
or connective tissue cleft, the joint cavity. A feature common to all forms of
edema, systemic or localized, is a disturbance in Starling’sg equilibrium, and,
therefore, one can analyze the pathophysiologic aspects of articular effusions
in terms of the colloid osmotic pressure of the plasma, the hydrostatic pressure in the capillary, the colloid osmotic pressure of the interstitial fluid and
the tissue tension.
Inflammatory edema like that of articular effusion in rheumatoid arthritis
is characterized by dilatation of the terminal vascular bed and marked increase in capillary permeability. The increased permeability and vasodilatation with associated increase in hydrostatic pressure result in the passage of
large amounts of fluid and protein including fibrinogen into the interstitial
space. Thus in terms of Starling’s equilibrium there is an increase in the
34
LIPSON, BALDES, ANDERSON, POLLEY
Table 3.-Comparison of Osmotic Pressure in Synovial Fluid in
Rhezrmatoid Arthritis Aflecting Both Knees
Osmotic Pressure
Case
Knee
Total, per cent NsCl
Colloid, mm. H20
1
Right
Left
0.879
0.874
Not done
2
Right
Left
0.859
0.858
Not done
6
Right
Left
0.878
0.879
162
160
15
Right
Left
0.872
0.872
Not done
Table 4.-Effect of Freezing (-70" C . ) on Colloid Osmotic Pressure
Colloid Osmotic Pressure, mm. HzO
Synovial fluid
Plasma
Sample
Refore freezine
After freezinr
Before freezina
After freezing
1
2
3
180
155
195
75
Not done
85
220
235
285
110
85
60
colloid osmotic pressure of the interstitial fluid due to the increased proltein
content and the increase in the interstitial fluid pressure secondary to excessive volume of interstitial fluid.
The specific role played by any of the forces of Starling's equilibrium in a
particular type of localized edema is difficult to assess. Nevertheless, an increase in the colloid osmotic pressure of the synovial fluid is frequently cited
as the principal etiologic factor in the formation and maintenance of joint
effusions.1-3
Relatively little data are available concerning the total or colloid osmotic
pressure of normal and abnormal synovial fluids. The average colloid osmotic
pressure of serum of cattle was found by Bauer, Ropes and Wainel to be 365
mm. HzO and that of bo\Tine synovial fluid to vary from 127 to 170 mm. HzO
with a mean of 150 mm. The colloid osmotic pressures of normal synovial fluid
from two humans were reported by Jensen and ZachariaelO to be 140 and
121 mm. H20, respectively.
The colloid osmotic pressure of rheumatoid synovial fluid before and after
intra-articular injection of hydrocortisone was studied by Makinen3 who reported a mean value of the colloid osmotic pressure before treatment was 424
mm. H 2 0 in 24 patients, whereas after treatment it decreased to 357 mm.
H20. An increase in the colloid osmotic pressure of synovial fluid was considered the principal causative agent in the formation of inflammatory efiusions in the synovial cavity.
In the one patient with degenerative arthritis of the knees studied by
Jensen and Zachariae,lo before and after the intra-articular administration of
OSMOTIC PRESSURE GRADIENTS
35
hydrocortisone, the colloid osmotic pressure of degenerative synovial fluid
increased from 113 mm. before the injection of hydrocortisone to 120 mm.
H,O 5 days following it. In the one paticnt with rheumatoid arthritis evaluated in a similar manner in the studies reported here (case 6, tables 1 and
3 ) , the colloid osmotic pressure of the synovial fluid in the left knee increased from 160 to 210 mm. H 2 0 following steroid instillation. Also during
the 5-day period following the injection of hydrocortisone into the left knee,
the colloid osmotic pressure of fluid from the right knee increased from 162 to
207 mm. H20, that of plasma increased from 317 to 430 mm. H20 and there
was an associated local articular (both knees) and general systemic improvement.
The results of our study suggest that the osmotic gradient is not the principal causative factor in the formation of effusions or the resorption of fluid
from the synovial cavity. Furthermore it appears that the osmotic gradient
between the plasma and synovial fluid would favor exit rather than entry
of fluid into the joint space. Recent studies have shown that the hydrostatic
pressure in a distended joint frequently exceeds the capillary hydrostatic
pressure.ll Thus, according to Starling’s equilibrium both the osmotic gradient
and tissue tension favor reduction rather than accumulation and maintenance
of excessive amounts of interstitial fluid. However, as pointed out by Bland,12
it is probable that Starling’s hypothesis is an oversimplification of what occurs
in a complex situation. Pappenheimer13 calculated that if diffusion were
limited to the filtering and absorbing areas as set forth in Starling’s hypothesis, transport would be inadequate to supply metabolic needs. He further
showed that water and solutes actually move rapidly in both directions across
the capillary wall.
Early in the pathogenesis of inflammatory edema other factors than those
outlined by StarlingQappear to play a role. The blockage of lymph vessels
by fibrin may be one of the most important. The lymph vessels are extremely
important in the removal of interstitial fluid and colloidal material from an
area of localized edema because lymph vessels do not collapse despite a
marked increase in tissue tension. This is the result of their connections to
collagen fibers14 which are separated by the accumulating edema fluid and
thereby tend to keep the lymph vessels open. However, if there is blockage
of the lymph vessels by fibrin plugs, this important exit may cease to function.15
The synovial cavity is supplied by superficial and deep lymphatic plexuses.l6
Partial or complete blockage of this important resorption system would favor
the entrance of fluid and solute at a faster rate than it can leave. The result
is effusion.
A possible explanation of our findings is that the osmotic gradient is in
reality being used as a part of a homeostatic mechanism to move fluid and
solutes out of the joint space in the presence of a plugged lymph system.
In support of this is the fact that inflammation of the synovial membrane
is associated with increased permeability which is subsequently reduced by
36
LIPSON, BALDES, ANDERSON, POLLEY
local intra-articular therapy.l7 More direct evidence has been provided by
isotope clearance studies by which Scholer, Lee and Polleyl* have shown that
the exit of D20 from the joint space was reduced in two of three rheumatoid
joints after intra-articular administration of hydrocortisone. Studies of the
clearance rates of injected r a d i o ~ o d i u r nand
~ ~ radioacti\Te iodine-labeled albuminZ0also demonstrated that rheumatoid knees had a higher clearance rate
than normal knees, whereas intra-articular injection of hydrocortisone and
clinical improvement were associated with a reduction of the clearance rate.
Thus, as a result of a variety of clearance studies and the osmotic pressure
observations reported here, the proposition that the osmotic gradient is working as a compensatory mechanism to mor7e fluid out of the inflamed joint becomes more tenable.
SUMMARY
The results of this study reveal that in rheumatoid joint disease the total
osmotic pressure of the synovial fluid tends to be lower than, or equal to, the
total osmotic pressure of the plasma. However, with local articular or general
systemic improvement in rheumatoid arthritis, the total osmotic pressure
of the synovial fluid and plasma tends to increase, and contrary to the sitnation prior to improvement the total osmo'tic pressure of the synovial fluid
may exceed that of the plasma.
The colloid osmotic pressure of the synovial fluid from joints of patients with
rheumatoid arthritis was consistently lower than the colloid osmotic pressure
of the plasma. The range was 145 to 285 mm. HzO for the synovial fluid with
a mean pressure of 197 mm., and from 220 to 430 mm. H,O for the colloid
osmotic pressure of the plasma with a mean value of 328 mm. Freezing ( -70"
C . ) the synovial fluid produced a decrease in the colloid osmotic pressure.
These results indicate that intra-articular fluid accumulates despite the existence of an osmotic gradient that should favor the reduction, rather than the
formation, of effusion. The possibility is suggested that the existing osmotic
gradient is a compensatory mechanism to move fluid out of the joint in the
face of blockage of the lymphatic system.
REFERENCES
1. Bauer, W., Ropes, M. W. and Waine,
H.: The physiology of articular structures. Physiol. Rev. 20:272, 1940.
2. Freyberg, R. H.: The joints. In Sodeman, W. A.: Pathologic Physiology:
Mechanisms of Disease, Ed. 3. Philadelphia, Saunders, 1961, p. 1033.
3. Makinen, P.: Synovial fluid in rheumatoid arthritis with special reference
to intra-articularly applied hydrocortisone. Ann. med. exper. et biol. Fenniae. (Suppl. 7 ) 36:1, 1958.
4. Ropes, M. W., Bennett, G. A., Cobb,
S., Jacox, R. and Jessar, R. A.: 1958
Revision of diagnostic criteria for
rheumatoid arthritis. Bull. Rheumat.
Dis. 9:175, 1958.
5. Losowsky, M. S., Alltree, E. M. and
Atkinson, M.: Plasma colloid osmotic
pressure and its relation to protein
fractions. Clin. Sc. 22:249, 1962.
6. Baldes, E. J. and Johnson, A. F.: The
thermo-electric osmometer: its construction and use. Biodynamica. No.
47:1, 1939.
7 . Reiff, T. R. and Yiengst, M. J.: A rapid
automatic semimicro colloid osmometer. J. Lab. & Clin. Med. 53:291,
37
OSMOTIC PRESSURE GRADIENTS
1959.
8. Pitts, R. F.: Physiology of the Kidney
and Body Fluids. Chicago, Yr. Bk.
Pub., 1963.
9. Starling, E. H.: On the absorption of
fluids from the connective tissue
spaces. J. Physiol. 19:312, 1896.
10. Jensen, C. E. and Zachariae, L.: The
contributions from hyaluronic acid
and from protein to the colloid osmotic pressure of human synovial
fluid. Acta rheum. scandinav. 5: 18,
1959.
11. Caughey, D. E. and Bywaters, E. G.:
Joint fluid pressure in chronic knee
effusions. Ann. Rheumat. Dis. 22:
106, 1963.
12. Bland, J. H.: Clinical Metabolism of
Body Water and Electrolytes. Philadelphia, Saunders, 1963.
13. Pappenheimer, J. R.: Passage of molecules through capillary walls. Physiol.
Rev. 33:387, 1953.
14. Greep, R. 0.: Histology. New York,
Blakiston, 1954.
15. Menkin, V.: The significance of lym-
phatic blockade in immunity. Ann.
New York A d . Sc. 46:789, 1946.
16. Bloom, W. and Fawcett, D. W.: A textbook of histology, Ed. 8. Philadelphia, Saunders, 1962.
17. Sharp, G. W. G.: Effect of certain antiarthritic compounds on the permeability of synovial membrane in the
rabbit. Ann. Rheumat. Dis. 22:50,
1963.
18. Scholer, J. F., Lee, P. R. and Polley,
H. F.: The absorption of heavy
water and radioactive sodium from
the knee joint of normal persons and
patients with rheumatoid arthritis.
Arth. & Rheumat. 2:426, 1959.
19. Harris, R., Millard, J. B. and Banerjee,
S. K.: Radio-sodium clearance from
the knee joint in rheumatoid arthritis. Ann. Rheumat. Dis. 17:189, 1958.
20. Ahlstrom, S., Gedda, P. 0. and Hedberg, H.: Disappearance of radioactive serum albumin from joints in
rheumatoid arthritis. Acta rheumat.
scandinav. 2: 129, 1956.
Richard L. Lipson, M.D., Fellow i n Biophysics, Mayo Foundation, Graduate School, University of Minnesota; Rochester,
Minnesota. Present address: Assistant Professor of Medicine,
Rheumatism Research Center, Unizjersity of Vermont College
of Medicine, Burlington, Vermont.
Edward 1. Baldes, Ph.D., Emeritus Member, Section of Biophysics, Mayo Clinic; Emeritus Professor of Biophysics, Mayo
Foundation, Graduate School, University of Minnesota; Rochester, Minnesota.
Joseph A. Anderson, B.S., Technical Assistant, Section of Biophysics, Mayo Clinic; Rochester, Minnesota.
Howard F. Polley, M.D., Consultant, Section of Medicine,
Mayo Clinic; Professor of Medicine, Mayo Founhtion, Graduate School, University of Minnesota; Rochester, Minnesota.
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