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Mammalian peripheral nerve sheath has unique responses to chronic elevations of endoneurial fluid pressure
EXPERIMENTAL
NEUROLOGY
70, 300-306 (1980)
Mammalian Peripheral Nerve Responses to Chronic Endoneurial Fluid PHILLIP Peripheral
A.
Low, Nerve
PETER
JAMES
Laboratory,
Mayo Received
Sheath Has Unique Elevations of Pressure
DYCK,
AND
Foundation, April
I,
JAMES
Rochester,
D.
SCHMELZER’
Minnesota
55901
1980
In acute experiments with fibroelastic tubes such as blood vessels there is alinear AP:AV relationship followed by a steeper AP:AV relationship for further increments of volume. Endoneurial fluid pressure (EFP) of peripheral nerve also increases with increases in endoneurial fluid volume. We monitored the effects of volume changes on AEFP during a protracted period of time (6 weeks to 1 year on 16 control and 16 experimental rats) to study if a similar relationship occurred in nerve. Nerves were rendered edematous using parenteral and oral galactose administration, EFP was monitored using an active servonull system, and endoneurial volume and subperineurial area (SPA) was measured on fixed tissue. Marked endoneurial edema was produced but EFP did not exceed 6 mm Hg at any time. There was a linear APp:AV relationship for a limited range of volumes followed by a reduced APp:AV slope. Because these changes evolved over a long time course we examined the response of AEFPIASPA as a function of time. There was an exponential reduction with time, thus underlying the importance of time-dependent processes in the production of a reduced AP:AV slope. We conclude that neuropathic changes are unlikely to be due to ischemia by compression of capillaries. Instead, in edematous states there is a very low shear modulus (i.e., a small AEFP produces a major volume change with time) and certain types of deformations appear very likely to cause demyelination. INTRODUCTION The endoneurium of mammalian compartment, having a blood-nerve
peripheral barrier,
nerve is a highly specialized a perineurial barrier, and a
Abbreviations: EFP-endoneurial fluid pressure, SPA-subperineurial area. 1 This work was supported in part by Center grants from the National Institutes of Health (NS14304), and the Muscular Dystrophy Association (12), and by Mayo, Borchard, Upton, and Gallagher Funds. 300 OO14-4886/80/110300-07$02.00/O Copyright D 1980 by Academic Press, Inc. All rights of reproduction in any form reserved.
MAMMALIAN
PERIPHERAL
NERVE
SHEATH
301
nerve-spinal fluid barrier. In certain clinical and experimental neuropathies there is a progressive increase in nerve volume and a progressive elevation in endoneurial fluid pressure (EFP) (4). In acute experiments with fibroelastic tubes such as blood vessels, a linear relationship between AV:AP (compliance ) (1,lO) occurs only for a limited range of volumes followed by a progressively greater APlAV with further volume increases (3). In experimental lead neuropathy, endoneurial edema continued to increase during at least 5 months (4, 7) but whether EFP increases proportionately or at an accelerating or decelerating rate for further volume increases is not known. Furthermore, the EFP changes beyond the first 5 months are not known. Because pressure changes in peripheral nerve sheath which are of low value and evolve during a long time may be quite different from that of the blood vessel, it seemed important to examine the effects of large volume changes for a protracted time on EFP changes in peripheral nerve. We recently addressed this question using the model of experimental galactose neuropathy and modified it to produce maximal edema. In experimental galactose neuropathy endoneurial edema is readily produced without causing fiber degeneration (12). METHODS Polyethylene matrix capsules (external diameter 0.5 mm) tightly wedged in tubing of the same material were implanted in the left sciatic nerve of 32 Sprague-Dawley rats and EFP recordings were made 1 month later using an active servonull system previously described (5). In brief, a micropipet containing 2 M saline forms one arm of a balanced AC wheatstone bridge. When the micropipet is wedged into a tubing connected to the capsule, the EFP causes a shift in the fluid interface generating an error voltage which is amplified and applied to a bellows system which generates a counterpressure within the pipet returning the interface to its original position. The hydraulic pressure is measured with a transducer and recorded on a chart. After the initial recordings, 16 rats were placed on a conventional diet containing 40% galactose, supplemented by three weekly intraperitoneal injections of 3 ml 40% galactose (galactose rats). The remaining 16 animals were pair-fed the same diet but without added galactose (control rats). The diets of both groups were vitamin supplemented. Endoneurial fluid pressure recordings were repeated at 6 weeks, 3 months, 5 months, and 12 months after commencement of feeding (galactose and normal rat pellets). Four animals were killed at each time interval and all morphological studies were done on the right sciatic nerve. In experimental neuropathies the time course of AEFP and AV extends over many months and because it is necessary to measure fascicular size on
302
LOW, DYCK,
AND SCHMELZER
FIG. 1. Transverse section of sciatic nerve from control (bottom) and galactose rat (top) after 6’weeks of galactose feeding (x498). Note the marked perivascular edema in the nerve of the galactose rat.
fixed tissue, it was possible to measure endoneurial area only at one time point for each animal. Endoneurial volume was therefore based instead on measurements of groups of control and galactose rats before and at
MAMMALIAN
PERIPHERAL
NERVE
SHEATH
303
specified times after poisoning. Compliance (AV/@) (1, 10) and derived moduli are therefore not directly comparable with those obtained on blood vessels. Assuming an insignificant change in nerve trunk length, the EFP might be related to fasicular area. Because the most consistent area of fluid accumulation is in the subperineurial space, we chose to measure subperineurial area (SPA) as an index of increased volume. The SPA of the major fascicle of right sciatic nerve was digitized on photographic enlargements (X 106) of transverse sections of nerves embedded in epoxy. RESULTS Marked edema was seen in all nerves examined (Fig. 1). It is seen from Fig. 2 that the relationship of EFP to SPA is best fitted by a sigmoid rather than a linear relationship (as would be expected if there were no compliance changes). The smooth curve (B-E) was computer-generated using the equation.
P = 0.8 mm Hg +
5 1 + (a/SPA)
’
where P = maximum EFP and a is a constant. The curve implies an average asymptote of 5.8 mm Hg with the foot and slope described by a constant and a second order power function. On Fig. 2, A and E are regions of minimal APIAV but for different reasons. E is a region where the vessel is most distensible, and A is a region occupied by controls where there is unstressed volume (lo), i.e., spaces that must be taken up by fluid before a pressure rise occurs. C is a region where hp increases approximately linearly with AV. B and D are transition regions. The EFP actually becomes less in spite of a tendency for the SPA to increase with time (Fig. 3). To examine this aspect we plotted AEFPIASPA at each time point against time (Fig. 4). There is an exponential reduction with time. y = 1.038 x lo5 In (-0.126x)
R2 = 0.545 DISCUSSION The EFP:ASPA relationship in these chronic experiments is dramatically different from that seen in acute experiments in other fluid-filled tubes such as arteries and veins. In the latter components A-C(see Fig. 2) occur followed by a steeper rather than flatter slope in E. The linear region C is thought to be due to elastic fibers in the vessel wall and the steep component is thought to be mainly due to collagen (3) which has a much
304
LOW, DYCK,
Oh
0.10 Area
AND SCHMELZER
0.15
(mm21
FIG. 2. Endoneurial fluid pressure as a function of subperineurial area. The relationship prior to galactose feeding is represented by A; APIAV is maximal at C and minimal at E after galactose feeding. B and D are transition regions. FIG. 3. The endoneurial fluid pressure does not change significantly with time in control rats (open circles), but is maximally increased at 6 weeks in galactose rats (closed circles) and tends to fall subsequently.
greater modulus of elasticity. The slope in E is likely to be due to the viscous properties of nerve sheath, similar to that described in longitudinal stretch beyond a certain length. However, a key difference from acute experiments is the marked timedependent changes which are analogous to the viscous modulus of blood vessels (8) but develop during a much greater period of time. The timedependent increase in compliance is ascribed to: (i) stress relaxation, i.e., less stress (AEFP) is needed with time to produce the same deformation
. azo-
n^
0.15 :
5 2
l .
0.10 . 0.05 -
.
.
06 0
2
* 4
, 9
6 lime (months)
. I wI2I IO
1D/* : -*--. . ...___ ;+3 0
6 Tine
9
I2
15
honthf)
FIG. 4. The subperineurial area as a function of time in controls (open circles) and galactosefed rats (filled circles). FIG. 5. There is an exponential decline in Aendoneurial fluid pressurelAsubperineuria1 with time. The curve is computer-generated using the exponential equation.
Y = 103.8 x 103 In (-0.126~) R2 = 0.545
area
MAMMALIAN
PERIPHERAL
NERVE
SHEATH
305
(ASPA); and (ii) creep (ll), i.e., with time, the same stress (AEFP) produces progressively greater deformation (ASPA). We synthesized our findings as follows. In the peripheral nerve sheath, the APIAV relationship is special in the low pressure and very long time course of hp and AV changes. With small increases in endoneurial fluid there is a linear increase in the EFP (analogous to an elastic modulus of 1.0 x lo5 dyn/cm2). Above 4 mm Hg EFP, the TFA increases with only minor increases of EFP (analogous to a creep and stress-relaxation dominated region of the compliance: time curve). The analogy, however, may be more apparent than real, because irreversible structural and permeability changes have been described in volume changes of this degree (2, 15). There are several applications of these findings to experimental and clinical neuropathies. The EFP was studied in neuropathies that evolve over days (9), weeks (present study), and months (10) and in none of these do pressures exceed 7 mm Hg, suggesting that Fig. 1 has wide application. A direct pressure effect of the EFP on nerve capillaries producing collapse and local ischemia has been advocated (14) as a mechanism of fiber degeneration in the entrapment neuropathies. This is unlikely to be true. A new finding is the very low shear modulus that occurs in peripheral nerve, i.e., a small change in the EFP produces a major change in the SPA. This very low shear modulus accounts for the ready prolapse of myelinated fibers when the perineurium is focally breached (13) and the prominent myelinated fiber distortion at the edges of applied pressure cuffs over peripheral nerve (6). It appears that focal distortion of fibers may be a cause of demyelination. REFERENCES 1. GLJYTON, A. C., H. J. GRANGER, AND A. E. TAYLOR. 1971. Interstitial fluid pressure. Physiol. Rev. 51: 527-563. 2. HAFTEK, J. 1970. Stretch injury of peripheral nerve. J. Bone Joint Surg. 52B: 354-365. 3. HINKE, J. A. M., AND M. L. WILSON. 1962. A study of elastic properties of a 550-p artery in vitro. Am. J. Physiol. 203: 1153-1160. 4. Low, P. A., AND P. J. DYCK. 1977. Increased endoneurial fluid pressure in experimental lead neuropathy. Nature (London) 269: 427-428. 5. Low, P. A., P. MARCHAND, F. KNOX, AND P. J. DYCK. 1977. Measurement of endoneurial fluid pressure with polyethylene matrix capsules. Brain Res. 122: 373377.
OCHOA, J., T. J. FOWLER, AND R. W. GILLIATT. 1972. Anatomical changes in peripheral nerves compressed by a pneumatic tourniquet. J. Anat. 113: 433-455. 7. OHNISHI, A., K. SCHILLING, W. S. BRIMIJOIN, E. H. LAMBERT, V. F. FAIRBANKS, AND P. J. DYCK. 1977. Lead neuropathy. 1. Morphometry, nerve conduction and choline acetyltransferase transport: new findings of endoneurial edema associated with segmental demyelination. Neuropath. Exp. Neurol. 36: 499-518. 6.
306
LOW,
DYCK,
AND
SCHMELZER
8. PETERSON, L. H., R. E. JENSEN, AND J. PARNELL. 1960. Mechanical properties of arteries in vivo. Circ. Res. 8: 622-639. 9. POWELL, H. C., R. R. MEYERS, M. L. COSTELLO, AND P. W. LAMPERT. 1979. Endoneurial fluid pressure in Walletian degeneration. Ann. Neurol. 5: 550-557. 10. ROTHE, C. F. 1978. Reflex control of the veins in cardiovascular function. Tutorial lecture presented at the American Physiological Society Fall Meeting, October 23, 1978, St. Louis, MO. 11. SARNOFF, S. J., AND E. BERGLUND. 1952. Pressure-volume characteristics and stress relaxation in the pulmonary vascular bed of the dog. Am. J. Physiol. 171: 238. 12. SHARMA, A. K., P. K. THOMAS, AND R. W. R. BAKER. 1976. Peripheral nerve abnormalities related to galactose administration in rats. J. Neural. Neurosurg. Psychiat. 39: 794-802. 13. SPENCER, P. S., H. J. WEINBERG, C. S. RAINE, AND J. W. PRINEAS. 1975. The perineurial window-a new model of focal demyelination and remyelination. Brain Res. 96: 323329. 14. SUNDERLAND, S. 1976. The nerve lesion in carpal tunnel syndrome. J. Neurol. Neurosurg. Psychiat. 39: 615-626. 15. WEERASURIYA, A., S. I. RAPAPORT, AND R. E. TAYLOR. 1979. Modification of permeability of frog perineurium to [‘VI-sucrose by stretch and hypertonicity. Brain Res. 173: 503-512.
NEUROLOGY
70, 300-306 (1980)
Mammalian Peripheral Nerve Responses to Chronic Endoneurial Fluid PHILLIP Peripheral
A.
Low, Nerve
PETER
JAMES
Laboratory,
Mayo Received
Sheath Has Unique Elevations of Pressure
DYCK,
AND
Foundation, April
I,
JAMES
Rochester,
D.
SCHMELZER’
Minnesota
55901
1980
In acute experiments with fibroelastic tubes such as blood vessels there is alinear AP:AV relationship followed by a steeper AP:AV relationship for further increments of volume. Endoneurial fluid pressure (EFP) of peripheral nerve also increases with increases in endoneurial fluid volume. We monitored the effects of volume changes on AEFP during a protracted period of time (6 weeks to 1 year on 16 control and 16 experimental rats) to study if a similar relationship occurred in nerve. Nerves were rendered edematous using parenteral and oral galactose administration, EFP was monitored using an active servonull system, and endoneurial volume and subperineurial area (SPA) was measured on fixed tissue. Marked endoneurial edema was produced but EFP did not exceed 6 mm Hg at any time. There was a linear APp:AV relationship for a limited range of volumes followed by a reduced APp:AV slope. Because these changes evolved over a long time course we examined the response of AEFPIASPA as a function of time. There was an exponential reduction with time, thus underlying the importance of time-dependent processes in the production of a reduced AP:AV slope. We conclude that neuropathic changes are unlikely to be due to ischemia by compression of capillaries. Instead, in edematous states there is a very low shear modulus (i.e., a small AEFP produces a major volume change with time) and certain types of deformations appear very likely to cause demyelination. INTRODUCTION The endoneurium of mammalian compartment, having a blood-nerve
peripheral barrier,
nerve is a highly specialized a perineurial barrier, and a
Abbreviations: EFP-endoneurial fluid pressure, SPA-subperineurial area. 1 This work was supported in part by Center grants from the National Institutes of Health (NS14304), and the Muscular Dystrophy Association (12), and by Mayo, Borchard, Upton, and Gallagher Funds. 300 OO14-4886/80/110300-07$02.00/O Copyright D 1980 by Academic Press, Inc. All rights of reproduction in any form reserved.
MAMMALIAN
PERIPHERAL
NERVE
SHEATH
301
nerve-spinal fluid barrier. In certain clinical and experimental neuropathies there is a progressive increase in nerve volume and a progressive elevation in endoneurial fluid pressure (EFP) (4). In acute experiments with fibroelastic tubes such as blood vessels, a linear relationship between AV:AP (compliance ) (1,lO) occurs only for a limited range of volumes followed by a progressively greater APlAV with further volume increases (3). In experimental lead neuropathy, endoneurial edema continued to increase during at least 5 months (4, 7) but whether EFP increases proportionately or at an accelerating or decelerating rate for further volume increases is not known. Furthermore, the EFP changes beyond the first 5 months are not known. Because pressure changes in peripheral nerve sheath which are of low value and evolve during a long time may be quite different from that of the blood vessel, it seemed important to examine the effects of large volume changes for a protracted time on EFP changes in peripheral nerve. We recently addressed this question using the model of experimental galactose neuropathy and modified it to produce maximal edema. In experimental galactose neuropathy endoneurial edema is readily produced without causing fiber degeneration (12). METHODS Polyethylene matrix capsules (external diameter 0.5 mm) tightly wedged in tubing of the same material were implanted in the left sciatic nerve of 32 Sprague-Dawley rats and EFP recordings were made 1 month later using an active servonull system previously described (5). In brief, a micropipet containing 2 M saline forms one arm of a balanced AC wheatstone bridge. When the micropipet is wedged into a tubing connected to the capsule, the EFP causes a shift in the fluid interface generating an error voltage which is amplified and applied to a bellows system which generates a counterpressure within the pipet returning the interface to its original position. The hydraulic pressure is measured with a transducer and recorded on a chart. After the initial recordings, 16 rats were placed on a conventional diet containing 40% galactose, supplemented by three weekly intraperitoneal injections of 3 ml 40% galactose (galactose rats). The remaining 16 animals were pair-fed the same diet but without added galactose (control rats). The diets of both groups were vitamin supplemented. Endoneurial fluid pressure recordings were repeated at 6 weeks, 3 months, 5 months, and 12 months after commencement of feeding (galactose and normal rat pellets). Four animals were killed at each time interval and all morphological studies were done on the right sciatic nerve. In experimental neuropathies the time course of AEFP and AV extends over many months and because it is necessary to measure fascicular size on
302
LOW, DYCK,
AND SCHMELZER
FIG. 1. Transverse section of sciatic nerve from control (bottom) and galactose rat (top) after 6’weeks of galactose feeding (x498). Note the marked perivascular edema in the nerve of the galactose rat.
fixed tissue, it was possible to measure endoneurial area only at one time point for each animal. Endoneurial volume was therefore based instead on measurements of groups of control and galactose rats before and at
MAMMALIAN
PERIPHERAL
NERVE
SHEATH
303
specified times after poisoning. Compliance (AV/@) (1, 10) and derived moduli are therefore not directly comparable with those obtained on blood vessels. Assuming an insignificant change in nerve trunk length, the EFP might be related to fasicular area. Because the most consistent area of fluid accumulation is in the subperineurial space, we chose to measure subperineurial area (SPA) as an index of increased volume. The SPA of the major fascicle of right sciatic nerve was digitized on photographic enlargements (X 106) of transverse sections of nerves embedded in epoxy. RESULTS Marked edema was seen in all nerves examined (Fig. 1). It is seen from Fig. 2 that the relationship of EFP to SPA is best fitted by a sigmoid rather than a linear relationship (as would be expected if there were no compliance changes). The smooth curve (B-E) was computer-generated using the equation.
P = 0.8 mm Hg +
5 1 + (a/SPA)
’
where P = maximum EFP and a is a constant. The curve implies an average asymptote of 5.8 mm Hg with the foot and slope described by a constant and a second order power function. On Fig. 2, A and E are regions of minimal APIAV but for different reasons. E is a region where the vessel is most distensible, and A is a region occupied by controls where there is unstressed volume (lo), i.e., spaces that must be taken up by fluid before a pressure rise occurs. C is a region where hp increases approximately linearly with AV. B and D are transition regions. The EFP actually becomes less in spite of a tendency for the SPA to increase with time (Fig. 3). To examine this aspect we plotted AEFPIASPA at each time point against time (Fig. 4). There is an exponential reduction with time. y = 1.038 x lo5 In (-0.126x)
R2 = 0.545 DISCUSSION The EFP:ASPA relationship in these chronic experiments is dramatically different from that seen in acute experiments in other fluid-filled tubes such as arteries and veins. In the latter components A-C(see Fig. 2) occur followed by a steeper rather than flatter slope in E. The linear region C is thought to be due to elastic fibers in the vessel wall and the steep component is thought to be mainly due to collagen (3) which has a much
304
LOW, DYCK,
Oh
0.10 Area
AND SCHMELZER
0.15
(mm21
FIG. 2. Endoneurial fluid pressure as a function of subperineurial area. The relationship prior to galactose feeding is represented by A; APIAV is maximal at C and minimal at E after galactose feeding. B and D are transition regions. FIG. 3. The endoneurial fluid pressure does not change significantly with time in control rats (open circles), but is maximally increased at 6 weeks in galactose rats (closed circles) and tends to fall subsequently.
greater modulus of elasticity. The slope in E is likely to be due to the viscous properties of nerve sheath, similar to that described in longitudinal stretch beyond a certain length. However, a key difference from acute experiments is the marked timedependent changes which are analogous to the viscous modulus of blood vessels (8) but develop during a much greater period of time. The timedependent increase in compliance is ascribed to: (i) stress relaxation, i.e., less stress (AEFP) is needed with time to produce the same deformation
. azo-
n^
0.15 :
5 2
l .
0.10 . 0.05 -
.
.
06 0
2
* 4
, 9
6 lime (months)
. I wI2I IO
1D/* : -*--. . ...___ ;+3 0
6 Tine
9
I2
15
honthf)
FIG. 4. The subperineurial area as a function of time in controls (open circles) and galactosefed rats (filled circles). FIG. 5. There is an exponential decline in Aendoneurial fluid pressurelAsubperineuria1 with time. The curve is computer-generated using the exponential equation.
Y = 103.8 x 103 In (-0.126~) R2 = 0.545
area
MAMMALIAN
PERIPHERAL
NERVE
SHEATH
305
(ASPA); and (ii) creep (ll), i.e., with time, the same stress (AEFP) produces progressively greater deformation (ASPA). We synthesized our findings as follows. In the peripheral nerve sheath, the APIAV relationship is special in the low pressure and very long time course of hp and AV changes. With small increases in endoneurial fluid there is a linear increase in the EFP (analogous to an elastic modulus of 1.0 x lo5 dyn/cm2). Above 4 mm Hg EFP, the TFA increases with only minor increases of EFP (analogous to a creep and stress-relaxation dominated region of the compliance: time curve). The analogy, however, may be more apparent than real, because irreversible structural and permeability changes have been described in volume changes of this degree (2, 15). There are several applications of these findings to experimental and clinical neuropathies. The EFP was studied in neuropathies that evolve over days (9), weeks (present study), and months (10) and in none of these do pressures exceed 7 mm Hg, suggesting that Fig. 1 has wide application. A direct pressure effect of the EFP on nerve capillaries producing collapse and local ischemia has been advocated (14) as a mechanism of fiber degeneration in the entrapment neuropathies. This is unlikely to be true. A new finding is the very low shear modulus that occurs in peripheral nerve, i.e., a small change in the EFP produces a major change in the SPA. This very low shear modulus accounts for the ready prolapse of myelinated fibers when the perineurium is focally breached (13) and the prominent myelinated fiber distortion at the edges of applied pressure cuffs over peripheral nerve (6). It appears that focal distortion of fibers may be a cause of demyelination. REFERENCES 1. GLJYTON, A. C., H. J. GRANGER, AND A. E. TAYLOR. 1971. Interstitial fluid pressure. Physiol. Rev. 51: 527-563. 2. HAFTEK, J. 1970. Stretch injury of peripheral nerve. J. Bone Joint Surg. 52B: 354-365. 3. HINKE, J. A. M., AND M. L. WILSON. 1962. A study of elastic properties of a 550-p artery in vitro. Am. J. Physiol. 203: 1153-1160. 4. Low, P. A., AND P. J. DYCK. 1977. Increased endoneurial fluid pressure in experimental lead neuropathy. Nature (London) 269: 427-428. 5. Low, P. A., P. MARCHAND, F. KNOX, AND P. J. DYCK. 1977. Measurement of endoneurial fluid pressure with polyethylene matrix capsules. Brain Res. 122: 373377.
OCHOA, J., T. J. FOWLER, AND R. W. GILLIATT. 1972. Anatomical changes in peripheral nerves compressed by a pneumatic tourniquet. J. Anat. 113: 433-455. 7. OHNISHI, A., K. SCHILLING, W. S. BRIMIJOIN, E. H. LAMBERT, V. F. FAIRBANKS, AND P. J. DYCK. 1977. Lead neuropathy. 1. Morphometry, nerve conduction and choline acetyltransferase transport: new findings of endoneurial edema associated with segmental demyelination. Neuropath. Exp. Neurol. 36: 499-518. 6.
306
LOW,
DYCK,
AND
SCHMELZER
8. PETERSON, L. H., R. E. JENSEN, AND J. PARNELL. 1960. Mechanical properties of arteries in vivo. Circ. Res. 8: 622-639. 9. POWELL, H. C., R. R. MEYERS, M. L. COSTELLO, AND P. W. LAMPERT. 1979. Endoneurial fluid pressure in Walletian degeneration. Ann. Neurol. 5: 550-557. 10. ROTHE, C. F. 1978. Reflex control of the veins in cardiovascular function. Tutorial lecture presented at the American Physiological Society Fall Meeting, October 23, 1978, St. Louis, MO. 11. SARNOFF, S. J., AND E. BERGLUND. 1952. Pressure-volume characteristics and stress relaxation in the pulmonary vascular bed of the dog. Am. J. Physiol. 171: 238. 12. SHARMA, A. K., P. K. THOMAS, AND R. W. R. BAKER. 1976. Peripheral nerve abnormalities related to galactose administration in rats. J. Neural. Neurosurg. Psychiat. 39: 794-802. 13. SPENCER, P. S., H. J. WEINBERG, C. S. RAINE, AND J. W. PRINEAS. 1975. The perineurial window-a new model of focal demyelination and remyelination. Brain Res. 96: 323329. 14. SUNDERLAND, S. 1976. The nerve lesion in carpal tunnel syndrome. J. Neurol. Neurosurg. Psychiat. 39: 615-626. 15. WEERASURIYA, A., S. I. RAPAPORT, AND R. E. TAYLOR. 1979. Modification of permeability of frog perineurium to [‘VI-sucrose by stretch and hypertonicity. Brain Res. 173: 503-512.