(Stroke. 1995;26:1240-1246.)
© 1995 American Heart Association, Inc.
Articles |
Neonatal Ischemic Neuroprotection by Modest Hypothermia Is Associated With Attenuated Brain Acidosis
From the Departments of Pediatrics (A.R.L.), Radiology (R.J.T.C.), and Pathology (D.B.), University of Texas Southwestern Medical Center at Dallas, and the University Medical Center of Southern Nevada, Las Vegas (R.S.).
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Abstract |
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Background and Purpose A 2.9°C reduction in the intraischemic rectal temperature of neonatal piglets is associated with less brain damage compared with animals with normothermic rectal temperatures. This investigation studied one potential mechanism for this observation: better maintenance of energy stores and less brain acidosis secondary to reduced metabolic activity associated with modest hypothermia.
Methods 31P MR spectroscopy was used to study piglets before, during, and after 15 minutes of partial brain ischemia with intraischemic rectal temperatures of either 38.3±0.4°C (n=10, normothermic) or 35.4±0.5°C (n=10, hypothermic). Animals were followed up for up to 72 hours after ischemia and were evaluated clinically and by brain histology.
Results Values for pHi remained 0.15 to 0.20 pH units greater in modestly hypothermic than in normothermic piglets during ischemia and the initial 30 minutes after ischemia (P=.049, group effect). Phosphocreatine, ß-ATP, and inorganic phosphorus were similar between groups. The relationship between the intraischemic energy state and subsequent clinical evidence of brain damage (irrespective of group assignment) revealed lower pHi over the last 7 minutes of ischemia for abnormal compared with normal piglets (5.98±0.22 versus 6.39±0.24, respectively; P=.002). In contrast, intraischemic ß-ATP (41±19% versus 57±21% of control) and inorganic phosphorus (273±31% versus 224±92% of control) for abnormal and normal piglets, respectively, did not differ between groups.
Conclusions Intraischemic modest hypothermia attenuates the severity of brain acidosis during and 30 minutes after ischemia compared with normothermic animals and supports the concept that attenuated brain acidosis is a potential mechanism by which hypothermia may reduce ischemic brain damage.
Key Words: acidosis • cerebral ischemia • hypothermia • spectroscopy, nuclear magnetic resonance
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Introduction |
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Hypoxic-ischemic encephalopathy in term and near-term human neonates is an important clinical syndrome that may be associated with subsequent neurodevelopmental deficits. Epidemiological analysis of cerebral palsy reveals diverse causes, of which perinatal events (intrapartum and neonatal) account for up to 20% of all cases.1 However, clinical management of neonatal hypoxic-ischemic encephalopathy is limited to supportive medical care, reflecting large gaps in understanding the pathogenesis of hypoxic-ischemic brain damage. This has prompted recent evaluation of new therapies to test the role of excitatory neurotransmitters, oxygen free radicals, and intracellular calcium in the development of brain damage.2 There also has been keen interest in the use of modest hypothermia (reductions in temperature of 2°C to 3°C) to provide neuroprotection. In multiple adult species such as rats,3 gerbils,4 dogs,5 and rabbits,6 modest hypothermia provided partial or complete ischemic neuroprotection when used in a protective and preservative manner (ie, hypothermia was initiated before and continued during the ischemic interval). A limited number of reports have provided similar observations in neonates. During hypoxia-ischemia decreasing axillary temperature by 2.5°C in 10-day-old Sprague-Dawley rats7 and lowering brain temperature by 3°C in 7-day-old Wistar rats8 was associated with a reduction in brain damage. We have also recently demonstrated that a 2.9°C reduction in intraischemic rectal temperature of neonatal piglets is associated with less brain damage compared with animals with normothermic rectal temperatures.9
A potential mechanism for the neuroprotection associated with intraischemic modest hypothermia is reduced metabolic activity with consequent better maintenance of energy stores and smaller reductions in pHi. This hypothesis was investigated by the use of 31P MR spectroscopy (MRS) to determine whether intraischemic modest hypothermia was associated with better preservation of brain energy state and pHi compared with normothermic animals. These measurements were performed in 21 piglets who were also the subjects of a previous report demonstrating the influence of relatively small changes in temperature on ischemic brain damage.9
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Materials and Methods |
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This investigation was approved by the Institutional Review Board for Animal Research at the University of Texas Southwestern Medical Center at Dallas. Details concerning the surgical preparation, experimental design, and outcome variables have been reported in detail and will be briefly summarized.9
Twenty-one piglets were instrumented 24 hours before the experiment with the use of aseptic technique. Anesthetic agents were ketamine (20 mg/kg IM) and pentobarbital (20 mg/kg IV). Catheters were positioned in the external and internal jugular vein and left common carotid artery and then tunneled to the piglet's back to be stored in a pouch. On the day of the experiment thiopental (20 mg/kg IV) was administered, and the animals were intubated and ventilated with inspired gases of 70% N2O and 30% O2. Vecuronium (0.25 mg/kg per hour IV) and nalbuphine HCl (0.15 mg/kg IV) were given for muscle paralysis and analgesia, respectively. Rectal temperature was monitored with a thermocouple microprobe, and a blood pressure cuff was positioned around the animal's neck.
After preparation, animals were transported to the Magnetic Resonance Laboratory, wrapped in a thermal blanket, and placed supine in a Plexiglas cylinder with the head resting on a rectangular 4x5-cm double-tuned (31P and 1H) surface coil10 ; the cylinder was then moved into the magnet bore for a 60- to 90-minute stabilization period. The experimental protocol consisted of a control period, 15 minutes of partial brain ischemia, and a 60-minute postischemic interval. In 10 piglets rectal temperature was maintained normothermic throughout, and in 10 piglets the same protocol was followed except that rectal temperature was reduced 2°C to 3°C (modest hypothermia) immediately before and during ischemia. Rectal temperature was altered by changing the temperature of the circulating water through the thermal blanket. Rectal temperature was used as an indicator of brain temperature based on our previously reported observations of brain temperature before, during, and after ischemia when rectal temperature was maintained constant at either 35.5°C or 39°C.9 Before brain ischemia brain and rectal temperature were approximately equivalent, with values within 0.5°C of each other for piglets with either rectal temperature. During ischemia there was a dissociation between brain and rectal temperature since brain temperature at a depth of 1 cm from the cortical surface decreased by 3°C in piglets maintained at either 35.5°C or 39°C rectal temperature. Immediately after ischemia brain temperature rapidly increased, and within 10 minutes of termination of ischemia, brain and rectal temperature closely approximated each other when rectal temperature was maintained at either 35.5°C or 39°C. Thus, groups with different intraischemic rectal temperatures can be used as an indicator of different brain temperatures. Brain ischemia was induced by inflation of a blood pressure cuff around the neck to 300 mm Hg and hemorrhage via a venous catheter to a mean arterial blood pressure (MABP) of approximately 30 mm Hg. After the postischemic interval animals were weaned from the ventilator, extubated, returned to their pens, and maintained for 72 hours. One piglet was used as a sham-operated control and underwent instrumentation and experimental observation without brain ischemia under normothermic conditions.
Heart rate, MABP, and arterial blood samples for blood gases, pH (pHa), hematocrit, and plasma concentrations of glucose were measured during control, at 4 and 12 minutes during the ischemic interval, and at 5 minutes, 30 minutes, 60 minutes, and 72 hours after ischemia. 31P MR spectra of piglet brain were acquired on a Nicolet NT-80 MR system equipped with a 30-cm-diameter bore TMR 32/200 superconducting magnet (Oxford) operating at 32.5 MHz for 31P and 80.3 MHz for 1H MRS. Magnetic field homogeneity was made optimal by shimming on the proton signal from brain. Each 31P MR spectrum was acquired over approximately 7 minutes with the use of a pulse acquire sequence. A transmission pulse of 45 microseconds preceded acquisition parameters of 256 milliseconds of acquisition time, 1.5 seconds of interpulse delay, sweep width of ±2000 Hz, 4K data points per free induction decay, and 256 free induction decay transients per spectrum. Spectra were processed by left shift removal of the first three data points in the accumulated free induction decay and by application of exponential multiplication (10-Hz line broadening) before Fourier transformation. Baseline straightening was performed with the use of an interpolation routine.
At 24, 48, and 72 hours after ischemia we performed a clinical neurological assessment using a modification of the Overall Performance Score, originally described by Leonov et al5 and adapted by Laptook et al.9 The Overall Performance Score evaluates the state of awareness; ambulatory abilities; muscle tone; abnormal movements; presence or absence of hyperventilation and seizures; response to noise, pain, and light; and the ability to feed. These scores were used to categorize each piglet as either normal or encephalopathic (mild, moderate, or severe). After 72 hours brains were perfused, fixed, and stored in a 10% solution of phosphate-buffered formalin as previously described.9 After immersion fixation, brains were cut in five axial sections at approximately 5-, 10-, 15-, 20-, and 25-mm depths from the superior surface of the cortex and processed and stained (hematoxylin and eosin) as previously described.9 Six piglets (5 normothermic, 1 modest hypothermia) died before 72 hours after ischemia, and brains were perfused and fixed as described above. Ischemic neuronal damage was evaluated by a neuropathologist (D.B.) blinded to group assignment and was based on the presence of nuclear pyknosis and karyolysis as well as cytoplasmic retraction and eosinophilia. Brains were scored on a scale of 0 to 4, as follows: 0, normal neuronal morphology; 1, scattered isolated ischemic neurons; 2, groups of ischemic neurons; 3, laminar necrosis; and 4, ischemic changes in almost all or all neurons. To facilitate comparison with the MRS results, a composite score for neocortex was derived from the sum of scores for the first two axial sections. Each axial section in turn represented a summation of scores for right and left sides of frontal, parietal, temporal, and occipital cortex. The maximum composite score was 64 (diffuse ischemic changes in all areas of neocortex surveyed).
Peak heights of MR spectra acquired during and immediately after ischemia were compared with the resonance peak height of control spectra and expressed as a percentage of control. We calculated pHi from the chemical shift of the inorganic phosphorus resonance peak relative to the phosphocreatine peak using the following equation:
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where x refers to the chemical shift of the inorganic phosphorus
peak.11 A repeated-measures ANOVA (SAS) was used to
compare brain metabolic and systemic variables of the normothermic and
modestly hypothermic groups. Results were considered significant at
P<.05 for group and time effects and P<.10 for
group-time interaction. A more liberal 
error of .10 was used when
testing for interaction due to the relative loss of power compared with
the test of main effects in both factorial and repeated-measures ANOVA.
The liberal strategy for the omnibus test of interaction was followed
by the conservative Bonferroni-adjusted multiple comparisons to
localize significant group-time interaction (with P<.0028)
and time effects (with P<.0033). Animals with and without
clinical evidence of brain damage were compared by means of a nonpaired
t test to determine whether composite histological scores,
brain phosphorylated metabolites, and pHi
differed during ischemia. Spearman's rank correlation was used
for categorical variables. All results are expressed as mean±SD.
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Results |
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Changes in systemic physiological variables, neurological performance, and brain histology have been previously reported9 and will be briefly summarized. Groups were identical in age (9±3 days), and two littermates were studied on the same day with one animal assigned to each group. At control normothermic and modestly hypothermic groups were similar in rectal temperature (38.3±0.2°C versus 38.3±0.3°C), MABP (90±11 versus 88±12 mm Hg), pHa (7.44±0.05 versus 7.42±0.05), and blood gases. Brain ischemia was associated with comparable reduction in MABP (31±5 versus 29±7 mm Hg) and pHa (7.21±0.09 versus 7.24±0.10) for normothermic and modestly hypothermic groups, respectively. By design intraischemic rectal temperature was maintained at either 38.3±0.4°C (normothermia) or 35.4±0.5°C (modest hypothermia). However, modest hypothermia extended into the first 15 minutes of the postischemic interval, and thereafter both groups were maintained normothermic. The postischemic interval was associated with comparable MABP and pH between groups. In both groups MABP was restored to values similar to those of control within 5 minutes of the termination of brain ischemia (96±10 and 102±23 mm Hg for normothermic and modestly hypothermic animals, respectively). In both groups pHa progressively increased after ischemia and at 60 minutes after ischemia was only modestly reduced from control values (7.39±0.05 versus 7.44±0.05 and 7.38±0.06 versus 7.42±0.05 for normothermic and hypothermic animals at 60 minutes after ischemia and control, respectively; P<.05). Throughout the entire experimental protocol, arterial CO2 tension was kept constant (mean values, 30 to 40 mm Hg), arterial O2 tension was greater than 100 mm Hg in all animals, and arterial plasma glucose concentration was similar between groups.
The changes in pHi are plotted in Fig 1
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Because spectra are acquired over 7 minutes, results are plotted at the
midpoint of each spectrum. At control pHi was similar
between groups with values of 7.01±0.08 and 7.04±0.06 in normothermic
and modestly hypothermic piglets, respectively. Induction of modest
hypothermia before ischemia did not alter pHi
(7.06±0.07). During ischemia and the initial 30 minutes after
ischemia, pHi remained 0.15 to 0.20 pH units
greater in modestly hypothermic than in normothermic animals. The
differences in pHi between groups during and immediately
after ischemia resulted in a group effect (P=.049).
There were no interactions between groups. The presence of a
group effect without interactions indicates that the pattern of
change in pHi during the experimental protocol was similar
between groups, but the magnitude of change was minimized in the
modestly hypothermic animals. By 60 minutes after ischemia
values for pHi were similar between groups and comparable
to control values.
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,
solid lines, n=10) and modestly hypothermic animals (
, dashed
lines, n=10). Each data point is derived from a spectrum acquired over
7 minutes with the value plotted at the midpoint of this interval.
During ischemia and for the first 30 minutes after
ischemia, brain pH was consistently higher in the modestly
hypothermic piglets compared with normothermic animals and gave rise to
a group effect (P=.049).
During the control period, spectra (Fig 2) were similar
between groups as evidenced by height ratios of phosphorus resonance
peaks (phosphocreatine/ß-ATP, 1.71±0.17 versus 1.64±0.21 and
inorganic phosphorus/ß-ATP, 1.58±0.36 versus 1.58±0.40 for
normothermic and modestly hypothermic groups, respectively). The
signal-to-noise ratio of ß-ATP at control was comparable between
groups (6.8±1.8 and 7.4±2.0 for normothermic and modestly hypothermic
groups, respectively). In both groups ischemia was associated
with reductions in phosphocreatine to negligible values by the last 7
minutes of ischemia (Figs 2 and 3; results are
plotted at the midpoint of the 7-minute spectrum). However, the
decrease in phosphocreatine was slower in modestly hypothermic compared
with normothermic piglets (54±19% versus 31±25% of control for
hypothermic and normothermic groups, respectively, over the first 7
minutes of ischemia; P=.0029 for the change
difference). In both groups ischemia was associated with the
same degree of brain energy failure as measured by the decrease in
ß-ATP during the last 7 minutes of this interval (43±18% versus
57±21% of control for normothermic and modestly hypothermic,
respectively; P=.10) and elevation in inorganic phosphorus
(252±70% and 237±75% of control for normothermic and hypothermic
groups, respectively; P=.73). After ischemia,
phosphocreatine, ß-ATP, and inorganic phosphorus rapidly returned to
control levels in each group, and there were no differences between
groups. Results from the one sham-operated animal indicated that
pHi values and levels of phosphorylated
metabolites remained unchanged from control throughout the observation
period.
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As described in our prior report,9
intraischemic modest hypothermia was associated with less
severe stages of encephalopathy (7 normal, 2 mild, and 1 severe
encephalopathy) compared with normothermia (3 normal, 1 mild, 1
moderate, and 5 severe encephalopathy; P=.023). Modestly
hypothermic animals had less histological damage in the neocortex at
0.5 cm beneath the brain surface (P=.048), the caudate
nucleus (P=.038), and the pons/midbrain (P=.04)
and the same direction of effect in neocortex at 1 cm beneath the
surface (P=.07) and the cerebellum (P=.07)
compared with normothermic animals. The sham-operated animal had normal
neuronal morphology. The relationship between the intraischemic
energy state and subsequent evidence of brain damage was explored by
grouping animals with respect to the presence or absence of a
postischemic encephalopathy (including animals with mild,
moderate, and severe involvement) independent of the assigned
temperature treatment. A composite histological score was derived for
each post hoc group. Composite neocortical histological scores for
normal and encephalopathic animals differed (6.6±9.9 versus 56.3±8.8,
respectively; P<.001). The relationship between MR
variables during ischemia and the development of subsequent
brain damage, defined by the post hoc groups, is plotted in Fig 4. To best approximate end-ischemic values of
brain phosphorylated metabolites and
pHi, results from spectra acquired during the last 7
minutes of ischemia were used. Piglets who subsequently
developed clinical evidence of brain damage had lower pHi
during the last 7 minutes compared with normal piglets (5.98±0.22
versus 6.39±0.24, respectively; P=.002). Furthermore, there
was an inverse correlation between categories of overall performance
score and pHi values during the last 7 minutes of
ischemia (r=-.81, P<.001) such that
increasing acidosis was associated with more severe degrees of
encephalopathy. However ß-ATP (41±19% versus 57±21% of control)
and inorganic phosphorus (273±31% versus 224±92% of control) for
brain-damaged and normal piglets, respectively, did not differ between
groups.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results of this investigation demonstrate that a 2°C to 3°C reduction in intraischemic brain temperature is associated with potentially important alterations in ischemic brain metabolism and subsequent partial neuroprotection in comparison to animals studied under normothermic conditions. As indicated by the group effect, intraischemic modest hypothermia resulted in higher pHi values consistently during ischemia and for at least 30 minutes after ischemia compared with normothermic animals. Although the magnitude of difference in pHi between groups is in the order of 0.15 to 0.20 pH units, the persistence of this finding during an interval of approximately 45 minutes may be critical in attenuating potential adverse effects of brain acidosis. Among animals of both groups, clinical and histological evidence of brain injury were associated with more severe intraischemic acidosis. The results suggest that brain acidosis may be critical in the pathogenesis of neonatal ischemic brain damage, and decreasing the extent of acidosis may represent an important neuroprotective effect of modest hypothermia.
In adults there is an important role of brain acidosis in the
pathogenesis of brain damage. Excessive intraischemic brain
acidosis and lactate accumulation is associated with adverse
neurological,12 metabolic,13 and
pathological14 outcomes after ischemia.
Conversely, methods to limit the extent of brain acidosis and lactate
accumulation (insulin, fasting) result in a more favorable neurological
outcome. It has been speculated that there may be a threshold
concentration of brain lactate (
20 µmol/g,15
correlating to a pHi of 6.216 ) that is
critical for the development of ischemic brain damage. A
precise mechanism by which acidosis induces brain damage has yet to be
clearly established.
In neonatal animals the role of brain acidosis in the development of tissue injury is less clear.17 Some studies suggest that excessive lactate accumulation and brain acidosis does not occur in neonates. For example, Vannucci et al18 in a series of elegant studies demonstrated that hyperglycemia during hypoxia-ischemia did not result in brain lactate concentration greater than 20 µmol/g and did not accentuate the extent of brain damage compared with normoglycemic animals.19 Variables such as a gradual fall in plasma and brain glucose of hyperglycemic rat pups during the interval of hypoxia-ischemia may have limited the extent of brain lactosis.18 In contrast, LeBlanc et al20 have shown that increasing plasma glucose concentration during hypoxia-ischemia exacerbates brain injury in newborn piglets. Recent studies in this laboratory demonstrated that piglets (age, 8±3 days) subjected to partial brain ischemia can generate levels of brain lactate in excess of 20 µmol/g and brain pHi less than 6.2.10 21 The ability of neonatal brain to generate excessively high levels of lactate and extreme acidosis has been further clarified by studies of agonal glycolytic rate. Results of agonal glycolytic rate in piglets during the first month of life demonstrated that newborn piglets are indeed less prone to brain lactosis compared with their older counterparts as a result of a slower agonal glycolytic rate.22 However, because of a lower rate of glucose utilization compared with transport, newborn piglets generate higher concentrations of brain lactate compared with older animals under steady-state hyperglycemic conditions.23 Under such hyperglycemic conditions newborn piglets have the same potential to generate a high brain lactate concentration as older animals, although newborns will attain this level more slowly.22 These results may provide the basis for the observations stated in our prior report that piglets with evidence of brain injury (irrespective of group assignment) were older (postnatal age, 11±3 days) compared with unaffected animals (postnatal age, 8±2 days; P<.05).9 As demonstrated in this report, piglets that sustained less damage were exposed to lesser degrees of brain acidosis. Comparison of the two experimental groups demonstrates the neuroprotective effect of modest hypothermia, and comparison of damaged versus unaffected animals suggests an age effect, potentially by modulating the extent of brain acidosis.
In the present investigation the effects of modest hypothermia are
similar to results obtained in adult animals. For example, in adult
cats complete ischemia was studied with core body temperature
of 27°C, 32°C, 34.6°C, and 38°C.24 Results for
groups studied at 27°C, 32°C, and 34.6°C were identical and were
pooled to form one hypothermic group. Minimum pHi values
during ischemia were 6.07±0.22 and 6.42±0.15 for normothermic
and hypothermic animals, respectively. The larger differences in
intraischemic pHi between normothermic and
hypothermic cats compared with newborn swine in the present study
may reflect greater reduction in core body temperature from
normothermia. However, it is unclear why core body temperature of
34.6°C to 27°C did not result in progressively more modest changes
in intraischemic pHi as a function of temperature.
After ischemia, differences in pHi between
hypothermic and normothermic animals gradually decreased during a
45-minute interval, similar to our results. In adult rats
forebrain ischemia has been studied with brain temperature
maintained at 33°C, 38°C, and 40°C.25 During
ischemia the fall in pHi occurred more slowly in
hypothermic compared with normothermic and hyperthermic animals.
Similar to our results in neonatal piglets, the extent of reduction in
pHi of rats was less in hypothermic animals (6.35) than
in the other two groups (6.25), but these differences did not
achieve statistical significance.
Evidence for changes in intraischemic phosphorylated metabolites with reductions in temperature has been readily demonstrated with profound hypothermia. In neonatal rats complete brain ischemia at 20°C compared with 37°C was associated with a prolongation of the half-life periods for ATP and phosphocreatine from 9 to 70 minutes and 7.5 to 9.5 minutes, respectively.26 In 23-day-old piglets circulatory arrest at 15°C compared with 37°C was also associated with a slower decay of ATP and phosphocreatine.27 Similar observations have been reported in adult animals.28 The effects of more modest reductions in temperature on ischemic brain have been less prominent. In adult cats24 and rats25 reduction in temperature of 4°C to 8°C from normothermic values of 38°C was associated with greater ATP levels only initially during ischemia and smaller elevations of inorganic phosphorus throughout ischemia. Available data in neonates are limited to rat pups subjected to hypoxia-ischemia, which resulted in complete depletion of ATP at 37°C and preservation of ATP at 29°C ambient temperature.29 In the present investigation values of phosphorylated metabolites during the last 7 minutes of ischemia did not differ between normothermic and modestly hypothermic groups, and only phosphocreatine differed between groups during the first 7 minutes of ischemia. This appears contrary to prior observations.26 27 28 Presumably, the modest reduction in temperature accounts for similar group values of ß-ATP, but it is acknowledged that values acquired during the last 7 minutes of ischemia in modestly hypothermic (57±21%) and normothermic (43±18%) groups are in the expected direction of temperature effect even though significance was not achieved (P=.10). It is possible that similar experiments performed at a higher magnetic field strength may improve signal-to-noise ratio and temporal acquisition of intraischemic results and potentially demonstrate a significant difference in ß-ATP between groups. Even though a modest temperature effect on ß-ATP cannot be definitively excluded, the results of this investigation clearly demonstrate the presence of a group effect for pHi extending from during ischemia to 30 minutes into the postischemic interval. If a pHi threshold for ischemic brain damage exists in neonates (as suggested for adults), then even attenuation of pHi values by 0.20 pH units during and after ischemia may be critical in determining the extent of subsequent damage.
The association between brain temperature, the extent of brain acidosis, and the severity of neurological injury clearly warrants further investigation. This is an important issue because there are multiple potential mechanisms by which temperature may modulate the extent of ischemia-induced brain injury. When used as a protective strategy, intraischemic hypothermia preserves ATP30 ; reduces abnormal ion fluxes,31 tissue acidosis,26 27 and excitatory neurotransmitter release32 ; and protects the fluidity of lipoprotein membranes.33 Future studies need to ascertain whether the link between modest hypothermia and the extent of brain acidosis is causally related to the observed neuroprotection.
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Acknowledgments |
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This study was supported by the United Cerebral Palsy Research and Educational Foundation Inc, the Southwestern Biomedical Magnetic Resonance Facility (National Institutes of Health grant P41-RR02584), and the Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas. The authors wish to acknowledge the expert technical assistance of Damian Garcia and Greg Tollefsbol and the secretarial support of Marilyn Dixon.
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Footnotes |
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Reprint requests to Abbot R. Laptook, MD, Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235-9063.
Received August 31, 1994; revision received December 7, 1994; accepted March 13, 1995.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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