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(Hypertension. 1997;29:992-998.)
© 1997 American Heart Association, Inc.
Articles |
Mechanical Stress of the Carotid Artery at the Early Phase of Spontaneous Hypertension in Rats
From Department of Internal Medicine (M.E.S.), Department of Pharmacology (S.L.), and Institut National de la Santé et de la Recherche Médicale (INSERM) U337 (H.D., I.B., K.C.-T., P.L., M.E.S.), Broussais Hospital, Paris, France; Department of Pathology, Meaux (France) Hospital (A.M.W.); and Department of Physiology, UFES, Victoria, ES, Brazil (R.S.C.).
Correspondence to Prof Michel Safar, Médecine Interne 1, Hôpital Broussais, 96 rue Didot, 75674, Paris Cedex 14, France.
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Abstract |
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Abstract Common carotid artery (CCA) hypertrophy has long been recognized in the neonatal period of development in spontaneously hypertensive rats (SHR), but the mean circumferential and shear stresses acting on the arterial wall have never been investigated in vivo. We investigated intra-arterial blood pressure in conscious rats, CCA diameter (echotracking techniques), blood flow velocity (pulsed Doppler), wall thickness (histomorphometry), and ganglionic blockade (hexamethonium) in Wistar rats and SHR at 5 and 12 weeks of age. During this interval, weight gain was identical in the strains, whereas the increase in wall thickness and blood pressure was greater in SHR. CCA diameter was identical at week 5 and increased similarly at week 12 in both strains. During ganglionic blockade, a larger diameter was observed in SHR at week 5 for the same BP level, whereas equivalent values were observed at week 12. Blood flow velocity decreased with age but to a significantly greater extent in SHR. Mean circumferential stress and shear stress index were identical in both strains at week 12. However, from weeks 5 to 12, mean circumferential stress increased with age similarly in both strains, whereas the age-related decrease in mean shear stress index was much greater in SHR than Wistar rats. Thus, despite a higher blood pressure, SHR exhibit the same carotid diameter as Wistar rats during early development. Because the kinetics of shear stress are different in both strains, altered flow-dilatation mechanisms, and possibly resulting endothelial dysfunction, may be involved in the diameter changes.
Key Words: rats, inbred SHR • hypertrophy • carotid artery, common • echotracking techniques • shear stress
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Introduction |
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In subjects with hypertension, large arteries are a major site of hypertensive complications, particularly for the coronary and cerebral circulations. The goal of drug treatment is to prevent such complications, which are generally attributed to, in addition to blood pressure (BP), an acceleration of the aging process, an association with atherosclerosis, or a combination of both factors.1 However, at an early period in both humans and rats, hypertensive large arteries are thicker and stiffer than those of normotensive controls.1 Whether the alterations of hypertensive arteries per se play a role in vascular damage and in its prevention by drug treatment and whether these alterations may be independent of age and atherosclerosis remain key unresolved problems. The basic assumption of most studies on large arteries in experimental hypertension is to consider that the observed arterial changes are the simple consequence of the mechanical effect of BP elevation on passive conduits.1 However, there are several arguments at the early phase of animal hypertension, particularly in genetic spontaneously hypertensive rats (SHR), suggesting that the effect of mechanical factors on the large conduit arteries is complex and even that neurohumoral factors have a major role in the arterial changes.
There is no complete agreement in the literature on the definition of the initial period of BP elevation in hypertensive rats. Depending on the methodology used for BP measurement, there are important discrepancies in the existence of a prehypertensive period, as noticed in various reviews.2 3 In contrast, modifications of arterial structure are known to occur very early in genetic hypertension. Carotid hypertrophy has been noted in SHR during the prenatal period,3 4 a period during which BP is difficult or even impossible to evaluate but changes in flow velocity and shear stress are certainly present and important to consider.5 On the other hand, in SHR between 9 and 12 weeks of age, a transient phase of increased cardiac output has been reported compared with Wistar (and not Wistar-Kyoto) rats in association with neurogenic hyperactivity.6 7 ß-Blockade may prevent increased cardiac output and neurogenic hyperactivity, but it does not prevent the development of high BP,8 indicating that increased sympathetic activity via trophic influences, increased blood flow via flow dilatation, or a combination of both may act on the large artery wall independently of BP changes. Finally, numerous studies of SHR smooth muscle cells in culture have noted that the multiplication rate of aortic cells is substantially augmented compared with that in normotensive controls, a finding which implies that nonhemodynamic factors of genetic origin are substantially involved in the development of the hypertensive arterial wall.9 10 11
Taken together, such observations suggest that at the early phase of genetic hypertension in rats, the role of mechanical factors, involving both circumferential and shear stresses on large arteries, should be reviewed in detail. These days, such studies are made possible by the use of new technologies for the investigation of arterial mechanical properties. First, intra-arterial BP can be measured with a high level of reproducibility in conscious animals.12 Second, high-resolution echotracking techniques have been developed,13 14 15 16 enabling one to evaluate with atraumatic procedures the pulsatile changes of arterial diameter in populations of normotensive and hypertensive rats. Finally, simultaneous measurements of blood flow velocity can be performed, thus allowing the concomitant evaluation of the influences of shear and circumferential stresses.
The purpose of the present study was to determine the circumferential and shear stresses of the common carotid artery (CCA) during the early development of hypertension in SHR. Four groups of rats were studied: very young (5 weeks old) and young (12 weeks old) SHR compared with normotensive Wistar rats. CCA diameters of SHR and Wistar rats were determined in the systolic-diastolic BP range, together with measurements of carotid blood flow velocity and wall thickness. At 5 weeks, arterial growth is not yet achieved, but an adequate innervation is present. At 12 weeks, arterial maturation is complete, and the established phase of hypertension has occurred in rat strains.17
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Methods |
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The study was performed in male SHR and male normotensive Wistar rats (Iffa Credo, Fréjus, France). The experiments involved both BP measurements in conscious rats and CCA diameter and blood flow velocity determinations over the range of pulse pressure studied. The latter experiments were performed with rats under pentobarbital anesthesia (50 mg/kg IP) and were followed by histomorphometric determinations. The procedures followed were in accordance with institutional guidelines.
Four different experiments were performed. In experiment 1, intra-arterial BP was measured in conscious, unrestrained 5- and 12-week-old Wistar rats and SHR. In experiment 2, intra-arterial BP (right carotid artery) and pulsatile changes of carotid diameter and blood flow velocity (left carotid artery) were measured at 5 and 12 weeks of age in anesthetized Wistar rats and SHR. Shear stress was calculated from mean diameter and blood flow velocity. In experiment 3, intra-arterial BP (right carotid artery) and pulsatile changes of diameter (left carotid artery) were measured in anesthetized 5- and 12-week-old Wistar rats and SHR. Carotid samples were taken at the end of the experiment for histomorphometry and determination of medial thickness. Circumferential stress was calculated from mean pressure, diameter, and thickness. In experiment 4, for evaluation of CCA diameter changes at nearly maximal vasodilatation without sympathetic reflex activation, intra-arterial BP and pulsatile changes of diameter were measured before and after hexamethonium in anesthetized 5- and 12-week-old Wistar rats and SHR.
For BP measurements in conscious animals,13 16 rats were anesthetized with pentobarbital 2 days before the experiment, and a catheter (PE-50 fused to PE-10, Clay Adams) was placed in the lower abdominal aorta (via the femoral artery) for direct measurement of arterial pressure. Arterial pressure was recorded with a pressure transducer (Statham P23 Db) and pressure processor (Gould Instruments). The catheter was filled with heparinized saline (50 U/mL) and was tunneled under the skin of the back and exited between the scapulae. The rats were then allowed to recover from anesthesia for 48 hours. Arterial pressure was measured in conscious, freely moving rats in their home cages. BP signal was recorded continuously on a four-channel digital audio tape recorder (Biologic DTR-1201) over 1 hour after at least 30 minutes of equilibration. At the same time, or while the tape was replayed, 30 minutes of the signal was sampled at 1 kHz and stored on a personal computer. An algorithm was developed on a personal computer for identification of cardiac cycles and calculation of each of them as previously reported.13 16
The CCA diameter–pressure relationship was established from the simultaneous recording of arterial diameter (left side) and BP (right side). The technique of arterial diameter measurements with the use of an echotracking device (NIUS-01, ASULAB SA) has been previously described and validated in humans and rats.13 14 16 Briefly, this device measures internal arterial diameter and its systolic-diastolic variations with a precision close to 50 and 1 µm, respectively. This degree of resolution is made possible by oversampling (5000 arterial diameter measurements per second) and averaging 16 consecutive cardiac cycles. Since this frequency is established as asynchronous with the instrument clock, the resolution of the measurements increases with the square root of the number of independent time intervals acquired. A 10-MHz transducer is stereotaxically positioned over the left CCA, 1 cm below the carotid bifurcation, with gel as a transmitting medium. The artery is merely exposed and not dissected, as reported in detail elsewhere.13 14 16 From the simultaneous and continuous signals of pulsatile changes in arterial diameter and BP, the computerized acquisition system fits the diameter-pressure curve within the diastolic-systolic range of BP and then calculates the diameter-pressure curve using an arc-tangent function and three optimal fit parameters as described by Langewouters et al18 and adapted by others.13 14 Mean diameter was integrated from the diameter-time curve. The reproducibility of the method has already been published.13 14 16 The mean intraobserver coefficients of variations were 3±1% and 6±2%.
Carotid blood flow velocity was measured with a 20-MHz directional
pulsed-Doppler system with miniaturized Doppler probes as previously
described.19 20 The Doppler probe was placed around the
left CCA (on the same side as for pulsatile diameter measurements) and
connected to a VF-1 system.20 In experiment 2, it was
verified that the lumen diameter did not change when the miniaturized
pulsed-Doppler flow probes were placed around the CCA. Indeed, in six
5-week-old rats and six 12-week-old rats, mean diameter was measured
before and after the flow probe was placed around the CCA. Respective
values were 810±25 and 812±30 µm and 1225±110 and
1163±32 µm. The blood flow velocity index (kilohertz) was
measured from Doppler shifts. An index of carotid blood flow was
calculated as the product of the blood flow velocity index and mean
carotid lumen cross-sectional area (millimeters squared per unit
length) calculated from the echotracking technique. An index of mean
shear stress was deduced from the Hagen-Poiseuille equation as
4
Q/3.14Ri3, where
is blood viscosity, Q is carotid blood flow, and
Ri is internal mean carotid
radius.21 In this formula, was considered as constant
and was ignored in the calculation, Q was considered to be
the carotid blood flow index, and Ri was
considered as half the mean internal carotid diameter.
For acute ganglionic blockade, bolus injections of hexamethonium (100 mg/kg IV) were given, as previously described.22 BP and arterial diameter were measured before and 15 minutes after hexamethonium administration, at which time steady levels of BP were achieved.
In experiment 3, morphological analysis was performed in different groups of Wistar rats and SHR according to standard techniques.23 The left carotid artery was removed, fixed at the rat's mean pressure in a 4% formaldehyde Tris-buffered saline solution (pH between 7.0 and 7.4), and embedded in paraffin. As previously described,23 medial thickness and medial cross-sectional area were quantified with an automated image processor (NS1500, Nachet-Vision) on the basis of morphological principles. Mean circumferential stress was calculated as MAPxMD/2h, where MAP is mean arterial pressure (millimeters of mercury), MD is mean carotid diameter (micrometers), and h is medial thickness (micrometers).21 As a consequence of the incompressibility of the artery, medial cross-sectional area does not vary with acute BP changes, so longitudinal stress was also calculated.21
Values are represented as mean±SE. To compare Wistar and SHR strains at different ages, we performed a two-way ANOVA (age effect–group effect). A value of P<.05 was considered significant.
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Results |
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Experiment 1
Table 1
shows that in conscious Wistar rats and
SHR, body weight and BPs (systolic, diastolic, mean, and pulse
pressures) increased with age (P<.001). In SHR,
significantly lower body weight values (P<.001) and higher
BP values (P<.001) were noted compared with Wistar rats.
The increase in BP with age was much more pronounced in SHR than Wistar
rats. The interaction was significant for systolic (P<.01)
and mean (P<.05) arterial pressures. In both strains, heart
rate was reduced with age (P<.001), but significantly
higher values were noted in Wistar rats (P<.001).
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Experiment 2
Table 2 shows changes in BP, carotid diameter,
blood flow velocity, and mean shear stress in the study rats. In
anesthetized rats, BP changes were similar to those reported in
conscious rats, with higher BP values in SHR than Wistar rats and a
more rapid increase with age in SHR, particularly for pulse pressure
(interaction: P=.009). Absolute values of carotid mean
diameter as well as their age-related increases (P<.0001)
were identical in both strains (interaction: P=NS). With
age, pulsatile change in diameter (absolute or relative values)
significantly decreased in both strains. This effect was significantly
more marked in SHR than Wistar rats (interaction: P=.05 and
P=.03, respectively). At week 4, blood flow velocity index
and mean shear stress index were slightly higher in SHR than Wistar
rats, although no significant group effect was observed. With age,
these indexes decreased significantly. Significant interactions
(P<.02 and P<.03, respectively) were observed,
indicating that the decreases in blood flow velocity and mean shear
stress indexes were significantly greater in SHR than Wistar rats.
Absolute values of carotid blood flow index increased significantly
(P<.0002) with age in both strains, with a slight
interaction (P<.05) that disappeared when blood flow was
expressed per unit of body weight.
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Experiment 3
Table 3 shows CCA hemodynamic and histomorphometric
parameters in the study rats. Wall thickness and medial cross-sectional
area were significantly increased in SHR compared with Wistar rats.
Whereas the age-related changes in diameter were similar in both
strains, the age-related changes in carotid thickness and medial
cross-sectional area were substantially more pronounced in SHR
(interaction: P<.0006 and P<.0001,
respectively) compared with controls. Circumferential and longitudinal
wall stresses were not significantly different in the two strains but
were significantly higher in older rats than younger rats. No
significant interaction was observed.
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Experiment 4
The Figure shows the CCA diameter–BP curve during
ganglionic blockade with hexamethonium. At week 5, diameter was
significantly greater (P<.01) in SHR than Wistar rats at
any given BP value. At week 12, this difference disappeared, meaning
that at the same BP, the two strains had the same diameter.
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Discussion |
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The present study has shown that in conscious rats, the values of intra-arterial BP at 5 and 12 weeks of age were significantly higher in SHR than Wistar rats. Furthermore, from week 5 to week 12, BP increased strikingly more in conscious SHR than Wistar rats. In association with BP changes, we observed that whereas the age-related changes in diameter and wall stress were similar in both strains, with similar values for diameter and circumferential and longitudinal wall stresses at week 12, the SHR were characterized by a consistently greater increase in carotid thickness and a much greater decrease in blood flow velocity and shear stress with age than Wistar rats. These findings show for the first time that changes in both shear and circumferential stresses are strongly associated with changes in CCA geometry and wall thickness at the early phase of arterial development in SHR.
Consideration of Methods
At the early phase of genetic hypertension, there are important
and well-known limitations on BP determination in small animals such as
rats. Whereas some authors have described a prehypertensive period, a
number of reports from other laboratories have indicated a
significantly higher BP in SHR than control rats before the weaning
period (3 weeks of age).2 3 17 24 25 26 . In several studies,
BP was measured as systolic BP at the tail artery. Because BP involves
a steady component (mean arterial pressure) and a pulsatile component
(pulse pressure) and because pulse pressure increases markedly from
central to peripheral arteries without a concomitant change in mean
pressure,21 27 the elevation of systolic BP, when measured
alone at the tail artery, may simply represent an abnormality of
pressure wave transmission without substantial elevation of aortic mean
BP. On the other hand, intra-arterial BP measurements in very young
rats are difficult to perform and often have required dissection of the
carotid artery and use of anesthetic agents, which are known to
potentially modify BP level.2 Finally, in the present
experiment, the use of intra-arterial BP measurements in conscious rats
clearly showed that the increase in pressure with age in young rats
occurred much more rapidly in SHR than Wistar controls.
In the present study, we used atraumatic procedures to examine carotid arterial mechanics, thus preserving the innervation and geometry of the carotid arterial wall. However, several factors could possibly compromise our determination of arterial diameter, such as the use of anesthesia with intraperitoneal pentobarbital; the lack of smooth muscle deactivation, which is necessary for an in vivo study; and the effects of intravascular pressure on vessel length. These criticisms have been analyzed in detail previously13 16 28 and are unlikely to significantly affect the accuracy and interpretation of the present findings. However, because during the period of development arterial length is expected to increase in parallel with body weight and height, we neglected to evaluate indexes of arterial stiffness, such as compliance, distensibility, and incremental modulus. Indeed, with the use of echotracking techniques, only cross-sectional and not volumic indexes can be calculated. We have previously shown that the exclusive calculation of cross-sectional and not volumic indexes alters substantially the differences in compliance and distensibility observed between SHR and normotensive controls.29
Another consideration in this study is the typically reduced body weight in untreated SHR compared with Wistar rats.30 If vessel size is proportional to the mass of tissue that it supplies, then the CCA would be expected to be smaller in SHR than controls because body weight is reduced in SHR. In contrast to body weight, however, we found that the age-related increase in carotid diameter and blood flow per unit weight occurred similarly in both strains. Therefore, it is unlikely that changes in body weight can account for the arterial differences observed in the studied groups.
In the present investigation, great care was given to the methods used for the demonstration of transient changes in carotid flow velocity and shear stress. First, we compared SHR with Wistar and not Wistar-Kyoto rats because the latter did not differ from SHR in terms of cardiac output changes.6 7 8 Second, mean shear stress was calculated from carotid blood flow and lumen cross-sectional area measured at the same time in vivo in anesthetized rats. In previous studies,19 20 the measurement of blood flow velocity alone obtained from miniaturized Doppler probes has been widely used as a direct index of blood flow, since lumen diameter was considered as constant. Since the latter assumption cannot be true during the development of young rats, we combined the diameter and flow velocity measurements on the same carotid artery using a validated technology (see "Methods"). In addition, since we measured only mean flow velocity, we limited the study to mean shear stress and did not try to calculate pulsatile stress. The same assumption was made for circumferential wall stress, in which the pulsatile component was ignored. For the calculation of wall stress, BP and carotid diameter were measured in conscious rats, whereas carotid wall thickness was determined in vitro from histomorphometry. In previous studies in humans, we showed that arterial wall thickness and medial cross-sectional area, measured by histomorphometry and expressed in terms of dry weight, were strongly correlated with the same determinations performed in vivo with validated echo-Doppler techniques.31
Consideration of Findings
Previous animal experiments on isolated in vitro vascular segments
showed a decrease of internal diameter in different arterial
territories of SHR, particularly at the level of the
CCA.32 Histological measurements have given variable
results. In the aortic and carotid arterial beds, Eccleston-Joyner and
Gray3 found no difference in the internal diameter of SHR
and Wistar-Kyoto vessels measured at the fetal and neonatal periods. In
the present in vivo studies, the use of anesthesia may have disturbed
diameter measurements through its action on the sympathetic nervous
system and smooth muscle tone.33 However, a major role of
anesthesia does not seem likely because at the established phase of
hypertension, we observed increased diameter in the hypertensive
population, whether in conscious humans or in anesthetized
rats.1 13 Second, whereas most previous diameter
measurements were made on isolated vessels (ie, calculated from the
length of the stretched arterial rings),32 34 35 we
measured in vivo diameters in vessels that remained in situ at their
operating pressures. Removing vessels and subsequently perfusing them
at nonphysiological pressures or stretching them to a certain tension
may produce important modifications of arterial geometry and structure.
Damage of endothelium, which is difficult to avoid during in vitro
dissection of vessel segments, could have different effects on the tone
of isolated vessels in Wistar and SHR strains36 37 but
obviously did not interfere in the present measurements. Thus, we
observed that despite a rapid and consistent increase in BP in SHR, the
CCA diameter and its age-related increase remained the same as in
controls: There was apparently no mechanical effect of the increase in
pressure distension on carotid caliber in SHR between weeks 5 and 12.
Since at week 12, Wistar rats and SHR had the same diameter for
significantly different BP levels, this result means that the
pressure-diameter curve of SHR was shifted toward higher BP values.
Because after hexamethonium the 5-week-old Wistar rats had
significantly lower diameters than the 5-week-old SHR for the same BP,
and because at week 12, for the same BP, carotid diameters became
identical, these findings strongly suggest that important structural
and/or functional modifications of the carotid arterial wall occurred
between weeks 5 and 12 in SHR.
At the initial phase of hypertension in SHR, a transient increase in
cardiac output has been reported.6 7 This change in flow
when high BP develops indicates that autoregulatory mechanisms occur
and contribute to returning blood flow toward normal
values.38 In the present work, carotid flow indexes and
mean shear stress index seemed slightly higher in SHR than Wistar rats
at week 4 (Table 2
), but mostly significant transient changes in flow
velocity and mean shear stress index occurred from weeks 5 to 12.
Indeed, flow velocity and mean shear stress index significantly
decreased in Wistar rats and SHR from weeks 5 to 12, but a much more
substantial decrease in flow velocity and mean shear stress index was
observed in SHR. Furthermore, these changes were not associated with a
parallel change in carotid diameter. Arteries are known to consistently
respond to chronic changes in blood flow velocity with an acute
vasomotor response—vasodilatation with increased flow and constriction
with decreased flow—that is followed by medial restructuring when the
flow changes persist.38 39 40 The present study shows that
between weeks 5 and 12, this mechanism was disturbed in hypertensive
rats. Because the mechanism of flow-dilatation requires endothelium
integrity, we speculate that an endothelial dysfunction occurred in
SHR. This interpretation is strengthened by several observations in the
literature: (1) When blood flow is restricted in one carotid artery of
the rat pup, this vessel shows a smaller diameter and less medial
tissue mass than the contralateral control artery.41 (2)
In normotensive animals at birth, the mechanism of flow dilation is
physiologically operating but is disturbed in deendothelialized
vessels. This mechanism contributes to modification of the diameter and
structure of arteries (particularly the carotid artery), mainly through
changes in the elastin content of the arterial
wall.5 42 43 Finally, we and others44 45
reported that in 12-week-old rats, removal of carotid artery
endothelium resulted in an increase in compliance and diameter, the
mechanisms of which involve the release of both nitrite oxide and
vasoconstrictive substances.45 Interestingly, after
endothelium removal, the increases in diameter and compliance reached
that of fully relaxed vessels in normotensive rats, although this
maximal effect was not obtained in SHR.45
In the present study, carotid hypertrophy was present at the early phase of development in SHR. Medial area–body weight ratios were also shown to be larger for SHR, suggesting the presence of greater medial mass per unit of body weight.2 3 Such observations strongly suggest that increased arterial growth is involved in the mechanism of carotid hypertrophy in SHR. This finding might agree with the previous observations of an increased multiplication rate of SHR aortic cells in culture.8 9 10 11 On the other hand, it should be noted that in the present investigation, if the BP elevation in SHR had been associated with a pure passive carotid dilatation, a much larger increase in carotid lumen and therefore wall thickness should have been observed to maintain circumferential and longitudinal wall stresses. Since circumferential wall stress was maintained within normal ranges in SHR, the weight of evidence suggests that other mechanisms contributed to counteract the increased arterial growth. Growth responses in the arterial wall do not depend on cellular properties alone; they are also influenced by several factors involving externally supplied trophic stimuli and growth-inhibitory influences.46 Shear stress–induced changes in endothelial function and arterial structure may contribute to the limitation of vascular growth in SHR. Several experimental studies support the hypothesis that the presence of a functional endothelium is essential for maintaining vascular smooth muscle in a nonproliferative state.47 48 49 Endothelium removal has been shown to stimulate intra-arterial DNA synthesis on carotid arterial smooth muscle cell cultures at the early phase of hypertension in SHR, whereas this result was not observed in arteries of 20-week-old SHR.50 Wall protein synthesis obtained from incorporation of [14C]isoleucine was not affected, indicating that endothelium selectively inhibited cellular proliferation while not affecting cell size.50
In conclusion, the present study has shown that at the early phase of development in SHR, active changes in the carotid arterial wall occur, particularly under the influence of alterations of shear stress, flow dilatation mechanisms, and presumably resulting changes in endothelial function. These mechanisms contribute, independently of BP, to the maintenance of normal carotid lumen diameter and circumferential wall stress. Such observations imply that the autoregulatory mechanisms that characterize hypertension operate at the sites of both small and large arteries and that this particular pattern is observed even in young SHR. The specific implications of large arteries in the autoregulatory mechanisms of hypertension had been predicted several years ago by Chau et al51 on the basis of studies of cardiovascular models in which human data of systemic hemodynamics were introduced using an original mathematical method. Whether the specific changes of the large arteries in hypertension are the early phase of future complications and/or favor the presence of atherosclerosis is still largely ignored and requires further investigation.
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Acknowledgments |
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This study was performed with the help of the Institut National de la Santé et de la Recherche Médicale (INSERM), Paris; the Ministry of Research; and Association Claude Bernard (Assistance Publique de Paris). We thank Anne Safar, who had responsibility for the manuscript.
Received July 1, 1996; first decision July 29, 1996; accepted October 23, 1996.
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