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1 Edward Mallinckrodt Department of Pediatrics and 2 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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"Autoresuscitation" (AR) is the spontaneous recovery from hypoxic apnea by gasping. We examined aspects of heart function in two situations: 1) the maturationally acquired failure of AR that is characteristic of SWR, but not BALB/c, weanling mice and 2) AR failure in BALB/c mice induced by repeated exposures to anoxia. We determined maturational changes in heart and liver glycogen. Unlike liver glycogen levels, heart glycogen levels in SWR mice differed from those in BALB/c mice. They were consistently much lower throughout maturation and reached a nadir during the brief period when SWR weanling mice are vulnerable to AR failure. Also, rate of cardiac glycogen utilization in vulnerable SWR mice was lower than that of same-aged BALB/c mice and was nil during the latter one-half of the gasping stage when heart function is critical for AR success. Therefore, because glycogen utilization reflects cardiac work, heart failure could explain AR failure in SWR weanlings. Additionally, the increase in hypoxic heart rate that occurs with maturation is developmentally delayed in SWR mice, and this may contribute to their AR failure. Cardiac glycogen was not fully depleted in BALB/c mice during repeated anoxic exposures, indicating other reasons for AR failure. We view these findings as a potential model for the age-related peak in incidence of sudden infant death syndrome.
hypoxia; sudden infant death syndrome; liver; gasping; apnea
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SPONTANEOUS RECOVERY from hypoxic apnea by gasping, termed autoresuscitation, ensures survival in a variety of situations that cause acute cerebral hypoxemia or eschemia (41). Furthermore, it has been suggested that failure to autoresuscitate may be the critical event linking prolonged apnea to fatality in certain cases of sudden infant death syndrome (SIDS) (17, 40). In past research we developed a mouse model for the study of autoresuscitation physiology (14, 15, 24-27). We have documented two situations in which autoresuscitation fails: 1) a developmentally acquired, transient failure occurring in 18- to 23-day-old weanling SWR, but not BALB/c, mice and 2) failure induced in BALB/c or SWR mice after repeated anoxic exposures (15, 24-26). In these prior studies we have found that failure to gasp is rarely a cause of failed autoresuscitation in either situation. This suggested that circulatory failure resulting from inadequate glycogen stores in heart and/or liver might be a cause of autoresuscitation failure.
In the present studies we have analyzed cardiac and hepatic glycogen in SWR and BALB/c mice as a function of maturation. Additionally, we determined rates of glycogen depletion in these tissues in mice breathing anoxic gas mixtures and evaluated the potential role of heart rate regulation in contributing to autoresuscitation failure. Our results offer a physiological explanation for autoresuscitation failure in weanling SWR mice on the basis of maturational changes in heart rate regulation, cardiac glycogen content, and glycogen utilization during hypoxia.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies were performed in SWR and BALB/c mice of various ages. Mice were obtained from Jackson Laboratories (Bar Harbor, ME) and were used within 1-7 days of delivery from the vendor or were reared from our own breeding pairs. All mice were treated similarly in terms of diet, environmental temperature and light-dark cycles. Young mice, including weanlings (18-23 days old), were kept with their mothers up until the time of study. They were housed in the Washington University animal facilities before study.
Procedures
Studies were performed in animals kept at 21°C room temperature, usually between 11:00 AM and 4:00 PM. Mice were studied according to three protocols. These studies were approved by the Washington University Committee Animal Research. The induction of hypoxia in unanesthetized animals was deemed humane because N2 inhalation results in rapid loss of consciousness and is recommended as a method of euthanasia for mice by the National Institutes of Health Committee on Care and Use of Laboratory Animals.Protocol I.
BALB/c and SWR mice were anesthetized with pentobarbital sodium (50 mg/kg ip), and, after the anesthetic had taken effect in eliminating
reflex activity (~4-6 min), the mouse was positioned in the
supine position and a broad midline incision was made in the thorax and
abdomen, exposing the heart and liver. The heart was
immediately lifted free of the thoracic cavity and rapidly frozen by
compressing the tissue between metal blocks mounted on forceps
precooled in liquid
N2. Immediately after
this, a sample of liver was taken in the same manner. Heart and liver
tissue were immediately placed in vials and stored in liquid
N2 and subsequently at
22°C until analysis for glycogen. Tissue was taken from 5-, 10-, 21-, and 34-day-old animals as well as adults (>40 days old). The period of autoresuscitation failure in SWR mice was previously reported to be 18-23 days of age, which corresponds to the time period when young mice can be weaned from the mother (24). Therefore, for uniformity, 21 days were chosen for study in this protocol. A total
of 162 BALB/c and 200 SWR mice were used.
Protocol II. One hundred fifty-eight BALB/c and 80 SWR 21-day-old animals were used in this protocol. Mice were injected with anesthetic as in protocol I. However, some animals were then used as controls, whereas others (littermates) were immediately exposed to 97% N2-3% CO2 delivered through a cylinder covering the animal's head as previously described (27). At onset of hypoxic apnea (occurring ~12 s after onset of N2 exposure), which coincides with onset of marked neurological depression (hypoxic coma), the heart and liver were harvested in the same manner as in protocol I.
Initially, an anesthetic dose of 50 mg pentobarbital sodium/kg was used, as in protocol I; however, considering the effects of barbiturates in reducing metabolic rate and in increasing the efficacy of autoresuscitation, we then used smaller doses (25 and 12.5 mg/kg) in mice before N2 exposure (25). In protocol II mice exposed to N2, we assumed that pentobarbital sodium would have slight effects on metabolism because absorption into the bloodstream would be minimal in the short amount of time (~15 s) between the injection and loss of consciousness after N2 exposure. However, if there were a drug effect on glycogen metabolism this should become apparent with the reduction in dosage. Subsequent inspection of glycogen values of animals given full and reduced anesthetic dosage showed no significant differences, indicating that anesthesia used in this manner had no detectable effect on glycogen stores. This use of anesthesia was deemed humane because surgery was performed only after loss of consciousness. A second group of SWR mice was removed from N2 at onset of hypoxic apnea and then given access to air and observed either until spontaneous gasping and autoresuscitation occurred or until autoresuscitation failed. Failed autoresuscitation was verified by continuing to observe the animal for 15 s after the apparent cessation of gasping because further gasping or survival after this time occurs rarely if at all (15, 26). As a comparison group for these SWR mice that failed to autoresuscitate, we exposed BALB/c mice to continuous anoxia until 15 s after apparent cessation of gasping activity. Tissues were then harvested as in protocol I. The third group of mice (BALB/c and SWR) comprised those that were successful in the initial autoresuscitation attempt. We used a previously published protocol for repeated anoxic exposure to produce autoresuscitation failure (15). After the initial exposure to N2, immediately after return of the eupneic breathing pattern but before full neurological and behavioral recovery, these mice were reexposed to N2 so as to produce return of hypoxic apnea and then were allowed access to air. This procedure was repeated until mice failed to autoresuscitate. In a smaller group of BALB/c mice, after one to four successful autoresuscitations, the mice were reexposed to N2 until hypoxic apnea occurred and then tissues were harvested. The average time from onset of the tissue harvesting procedure until actually freeze clamping the heart (~13 s) or liver (~16 s) was kept to a minimum. To estimate the rate of glycogen consumption during hypoxia, we took into account this time delay along with the 15-s period after cessation of gasping as well as the durations of the hyperpnea, apnea, and gasping phases taken from our prior published studies in BALB/c and SWR mice in addition to control glycogen values and those during the course of a single anoxic exposure (13, 14, 26). Because tissue harvesting began at onset of hypoxic apnea but was not completed until 13-16 s thereafter, glycogen consumption was estimated for the period up to and then after the middle of the gasping phase.Protocol III. Previously unreported values for resting heart rate and heart rate at onset of hypoxic apnea were determined from electrocardiogram recordings of SWR mice exposed to 97% N2-3% CO2 that were performed during prior studies of BALB/c and SWR mice in which a protocol very similar to that in the present study was used (15, 26). Studies from 22 juvenile and 23 adult SWR mice were available for analysis. For the purposes of comparing rates of maturation of cardiac regulation in SWR mice, these values were compared with the previously published values for BALB/c mice (14).
Glycogen assay. Glycogen was measured by the amyloglucosidase enzyme method and expressed as micromoles per gram of wet weight (30, 32).
Statistical analysis. ANOVA and, when appropriate, the Bonferroni-Dunn t-test for multiple comparisons, were used in the analysis of data.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Changes in cardiac and liver glycogen content during maturation
(protocol I) are shown in Figs.
1 and 2. A
marked postnatal fall in cardiac glycogen was noted in both SWR and
BALB/c animals. Cardiac glycogen leveled off (BALB/c) or reached a
nadir (SWR) at 21 days of age. A gradual rise in glycogen levels
occurred after 21 days in SWR mice. Up until and including 34-day-old
mice, cardiac glycogen values in SWR animals were markedly lower than those in BALB/c mice. This disparity was marked at 21 days but disappeared after 34 days of age. In contrast, liver glycogen values
were lowest in 5- and 10-day-old mice; however, by 21 days of age,
glycogen content had more than doubled to reach adult levels (Fig. 2).
There were no significant differences in liver glycogen stores between
the two strains of mice.
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In protocol II, after exposure to
hypoxia there was a rapid decrease in cardiac glycogen in both SWR and
BALB/c weanling mice (Fig. 3). The
estimated rate of glycogen utilization during the hyperpneic and early
gasping phases was ~50% higher in BALB/c compared with SWR mice
(Fig. 4). Thereafter, in BALB/c mice,
glycogen utilization continued, although at a reduced rate, during the period of time from shortly after onset of gasping until shortly after
the last spontaneous gasp, a time during which the mice normally could
have autoresuscitated had they been exposed to room air. In SWR mice,
however, during the corresponding time period estimated glycogen
utilization was nil.
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Only 3 of the 22 SWR weanling mice that were exposed to air at onset of hypoxic apnea successfully autoresuscitated. Only one of the three was able to autoresuscitate a second time after a repeat hypoxic exposure. In contrast, all of the 43 BALB/c mice, exposed to air at onset of hypoxic apnea, autoresuscitated repeatedly with an average of 5.7 ± 1.2 (SE) autoresuscitations before succumbing to repeated anoxic exposures. After one or more anoxic exposures in mice that successfully autoresuscitated, there was no further evidence of decline in cardiac glycogen in either SWR or BALB/c mice, including animals that failed to autoresuscitate after repeated anoxic exposures (Fig. 4).
Unlike cardiac glycogen, hepatic glycogen stores were little affected
by one or two exposures to hypoxia and only became noticeably depleted
in BALB/c animals failing to autoresuscitate after four or more
exposures (Fig. 5).
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The maturational change in hypoxic bradycardia previously reported in
BALB/c mice, in which the intensity of the bradycardia at onset of
hypoxic apnea diminishes with age, was delayed in SWR mice and not
until adulthood did values become equivalent to those in BALB/c mice
(Fig. 6).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present studies extend our past investigations of potential mechanisms of failed autoresuscitation in mice (15, 25, 26). Autoresuscitation results from the integration of many physiological functions (8, 17, 34, 38). When autoresuscitation fails, presumably one or more of the several participating organ systems has failed. Withdrawal of atmospheric oxygen initially stimulates respiratory, cardiac, and motor activity. Then, with severe hypoxemia (arterial PO2 <10 Torr) an abrupt reduction in the activity and energy consumption by all major organs occurs, particularly in the brain, heart, and respiratory muscles at onset of hypoxic apnea, bradycardia, and coma (41). A transition from oxidative to anaerobic metabolism takes place not only in these organs but also in the body as a whole. Carbohydrate, stored as glycogen, becomes a primary fuel source, and reduced energy consumption by the heart and other organs, when combined with sufficient glycogen stores, increases the duration of survival during anoxia (22, 31, 35). However, ultimate survival requires reoxygenation of the blood. Although gasping, which originates in the brain stem and is dependent on anaerobic metabolism, can persist for a limited time in the absence of brain perfusion, sufficient pulmonary and systemic circulation is required to transport oxygenated blood to the heart and brain for recovery of normal functions. This conclusion is supported by the often-repeated observation that successful autoresuscitation, or for that matter artificial resuscitation by mechanical ventilation, requires a small but definable level of heart function as reflected in systolic blood pressure (1, 6, 7, 16, 34, 38, 39). Thus, in successful autoresuscitation, respiratory and cardiovascular functions are coordinated and interdependent. Therefore, although there are numerous theoretical causes of autoresuscitation failure, two primary causes are failure of the hypoxic heart to provide adequate tissue perfusion and failure of gasping to inflate the lungs.
The present data confirm our past finding that SWR weanling mice often are unable to autoresuscitate after a brief anoxic exposure and contrast in this respect with BALB/c weanlings (15, 24-26). Our past studies of autoresuscitation failure in SWR weanling mice ruled out failure of gasping as the source of failure in most cases (24-26). In past work, failure of the expected increase in heart rate ("cardiac resuscitation") despite vigorous gasping led us to suspect that oxygenated blood never reaches the cardiac pacemaker cells in the dying SWR mice, suggesting that inadequate systemic or pulmonary perfusion might be the cause of autoresuscitation failure (25). In support of this concept, in prior work we found that anoxic survival (i.e., time from onset of exposure to anoxia until the last gasp) was much shorter in SWR than in BALB/c weanlings (13). This is very relevant to our present findings because anoxic survival in the young of several species, including mice, is known to be linearly related to myocardial glycogen content, a relationship based on energy requirements of the anaerobic working heart and the importance of brain stem perfusion for sustained gasping (35). Consistent with these past observations, our present findings confirm that cardiac glycogen content is substantially lower in SWR compared with BALB/c weanling mice. Although cardiac glycogen in adult and infant mice was comparable to previously reported values, of particular relevance was the present observation in SWR mice that glycogen reaches a developmental nadir at 21 days and at this point is well below levels previously reported for mice and other species (4, 18, 20, 35, 42). Assuming that a critical level of myocardial glycogen may be needed for successful autoresuscitation, such a nadir during maturation could explain the previously documented period of vulnerability ranging from 18 to 23 days of age in SWR mice.
Estimated rates of glycogen utilization during anoxia provide additional evidence that insufficient glycogen is a primary cause of resuscitation failure in SWR weanling mice. Numerous studies of cardiac metabolism under anoxic or severely hypoxic conditions indicate that the primary source of the high-energy phosphate substrates required for muscle contraction is derived from glycolysis utilizing myocardial glycogen as the main source of glucose (31). It has been shown that, in the otherwise healthy anoxic heart, work performed is proportional to glycolytic rate, which in turn is closely correlated with rate of glycogenolysis (9, 10, 12, 29). Consequently, the finding that glycogen utilization is reduced in SWR compared with BALB/c mice during the period from onset of hypoxia to early gasping and, furthermore, that such utilization is nil during the last one-half of gasping strongly suggests that cardiac output was comparatively low at gasping onset in SWR animals and was negligible for much of the gasping period. Such an inference accounts for our previous observation of decreased gasping duration in SWR weanlings compared with BALB/c because brain stem perfusion is a primary factor in prolongation of gasping (22, 35, 37). Given the importance of cardiac function to autoresuscitation, this inference also can adequately explain the failure of autoresuscitation in many SWR weanlings. In mice that fail to autoresuscitate, as in other species exposed to anoxia, the cardiac electrical activity that persists long after gasping ceases likely reflects the increased glycogen stores in pacemaker and conducting tissues; however, this activity does not indicate effective cardiac output (6, 11). On the other hand, one must assume that a sufficient level of circulation is present at the onset of gasping in some SWR weanlings to explain the successful autoresuscitation that occurs in these individuals.
A second aim of our study was to investigate the possibility that glycogen depletion accounts for autoresuscitation failure after repeated anoxic exposures. The data indicate that, after the first anoxic exposure, cardiac glycogen levels stabilize with no evidence of significant depletion occurring in subsequent exposures. Because glycogen levels stabilize after the first successful autoresuscitation, a case cannot be made for depletion of glycogen stores being the major factor in this type of autoresuscitation failure. Several factors may account for this stabilization of cardiac glycogen stores. After the first exposure to anoxia, we have observed in this and in our prior studies that generalized motor activity during the hyperpneic phase of subsequent autoresuscitations is greatly diminished (15). A corresponding decrease in cardiac output during hyperpnea would conserve cardiac glycogen. Late-occurring increases in hypoxic redistribution of perfusion may also increase cardiac efficiency during repeated anoxic exposures (17). Also, it is known that depletion of cardiac glycogen rapidly promotes increased glycogen synthesis (20, 29). Glycogen synthesis occurring during the brief recovery periods after autoresuscitation may have been sufficient to compensate for the glycogen metabolized during anoxia. Additionally, after repeated anoxic exposures, our data indicate that glycogenolysis in liver finally occurs and release of glucose into blood would then be available for synthesis of cardiac glycogen. Our observations are consistent with past work by others indicating that glycogenolysis in the liver, unlike that in the heart, occurs only after long sustained or repeated hypoxia (18, 37). In prior work we have noted that autoresuscitation failure after repeated anoxic exposures is related to onset of heart block, which results in unremitting bradycardia despite persistent gasping (15). Therefore, either localized depletion of glycogen within pacemaker cells or, more likely, accumulation of adenosine and lactic acid, which causes heart block, inhibit glycolysis, and reduce myocardial contractility, may play the major role in this late-occurring type of autoresuscitation failure (3, 10, 31).
It has long been known that liver glycogen is relatively high in the fetus and then rapidly falls during the first 24 h after birth, only to gradually rise again with maturation. The developmental time course for change in liver glycogen that we found is similar to that previously reported in mice and other species (5, 20, 37). Noteworthy is the close similarity between SWR and BALB/c mice in this regard. These observations contrast with the observed changes in cardiac glycogen and is in keeping with observations by others, indicating that regulation of glycogen metabolism is highly organ specific (18, 20, 37). It is well known that cardiac glycogen is also elevated in the fetus but, unlike liver glycogen, the postnatal decrease is gradual (37). This postnatal decrease has often been studied; however, the transition period from infant to adult during weaning and late infancy has received little attention. To our knowledge our findings in SWR mice constitute the first evidence of a nadir in cardiac glycogen occurring during development. Our observation that cardiac glycogen levels were consistently lower in SWR than in BALB/c mice until maturation is completed again illustrates the age and organ specificity of glycogen-regulating mechanisms.
The present data indicate that cardiac glycogen levels in adult BALB/c mice are not a great deal higher than that of SWR weanlings, and yet our past research indicates that BALB/c adults autoresuscitate very effectively (14, 15). Prior research on autoresuscitation has focused primarily on fetal and infant mammals. However, some adult nonmammalian species (birds) have well-sustained hypoxic gasping, and many, although not all, of the adult mammals that have been examined autoresuscitate effectively despite relatively small cardiac glycogen stores and short anoxic survival times (2, 17, 21, 26, 28). This apparent paradox may be explained by considering the overall maturational changes occurring in the autoresuscitation mechanism. As maturation progresses in mice and other species, the basal energy consumption of brain tissue increases markedly, and, concomitantly, susceptibility of the brain to temporary or permanent injury during anoxia increases (22, 23). Consequently, mechanisms facilitating rapid autoresuscitation are required if the adult brain is to be spared from injury. Therefore, it is not surprising that our prior maturational studies of BALB/c and SWR mice have shown that the time taken to successfully perform autoresuscitation decreases during maturation (14, 25). These studies indicate that two factors that likely contribute to this more rapid autoresuscitation are increased heart rate at gasping onset and increased gasping rate (14). Others have demonstrated that adults, compared with infants, require increased blood pressure at gasping onset for autoresuscitation to be successful and that increased heart rate is likely required to support this increased pressure (6). At the cellular level, maturational changes in expression of oxidative phosphorylating enzymes in heart muscle may also contribute to rapid autoresuscitation (19). Importantly, regarding maturation of the autoresuscitation mechanism in mice, we have previously found that SWR weanlings, unlike same-aged BALB/c mice, have not yet acquired the adult mouse's capacity for rapid autoresuscitation (25). In part, this may be due to the fact that, although both BALB/c and SWR weanlings have relatively slow initial gasping rates compared with adults, SWR weanlings, as the present data indicate, still retain the marked bradycardia at onset of gasping that characterizes younger mice and are unlike BALB/c weanlings in this respect. Thus SWR weanling mice appear to have reached a critical developmental hiatus with regard to autoresuscitation. Their very low store of cardiac glycogen is evidence of age-appropriate maturation even to the point of overshooting and falling below adult levels. However, when SWR weanlings successfully autoresuscitate they take twice the time than an SWR adult takes (25). Therefore, they remain immature with respect to the adult's capacity for rapid autoresuscitation, and this, at least in part, may be due to persistent immaturity of heart rate regulation during hypoxia. The combination of a retained slow autoresuscitation mechanism that requires increased cardiac glycogen to support heart function and a premature fall in glycogen stores could be combined factors in autoresuscitation failure in SWR weanlings.
Clinical Relevance
Episodes of potentially reversible cerebral anoxia or ischemia are common threats to life in humans. Although especially common at birth, such threats persist into adulthood. Situations in which autoresuscitation is responsible for recovery in infants include "blue breath-holding spells," idiopathic apnea, and spasms of continuous coughing (as in pertussis infections) (40, 41). In older children and adults, autoresuscitation can cause recovery after partial drowning, cardiac asystoles (Stokes-Adams attacks, "pale breath-holding spells"), epileptic seizures, and sleep apnea (41). In studies of severe breath-holding spells, it is well documented that autoresuscitation persists as both a highly effective and a commonly employed mechanism for survival in children well past infancy. Idiopathic apnea producing acute hypoxemia is relatively common in infants under 1 yr of age and is believed to play a role in some forms of SIDS (40). Undetected prolonged apnea that is fatal (a situation resulting in a diagnosis of SIDS) presumes a failure of autoresuscitation. In fact, terminal gasping, without autoresuscitation, has been reported in infants dying of SIDS, an observation that has been verified by more recent studies of polygraphic data from infants who died of SIDS while undergoing cardiorespiratory monitoring at home (36, 43). The distinctive age distribution of SIDS, with a well-defined peak incidence at 2-4 mo of age, is a cardinal feature and one that has been unusually difficult to explain. The maturational changes occurring in the autoresuscitation mechanism in mice, and particularly the relatively brief transient deficiency in this mechanism occurring in young SWR mice, is a potential model for an age-related peak incidence of infant deaths due to various kinds of apnea. Abnormalities in heart rate regulation have been identified in SIDS victims (33). However, it is yet to be determined whether this might affect capacity for autoresuscitation or whether maturational changes in the mouse's autoresuscitation mechanism are similar to those of humans.| |
ACKNOWLEDGEMENTS |
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The authors acknowledge Dr. John O. Holloszy for advice and assistance with glycogen determination and the expert technical help of Sheila Kohlman and Martha Jennings.
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FOOTNOTES |
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This work was funded by National Institute of Child Health and Human Development Grant HD-10993.
Address for reprint requests and other correspondence: B. T. Thach, Div. of Newborn Medicine, Dept. of Pediatrics, Washington Univ. School of Medicine, One Children's Place, St. Louis, MO 63110. E-mail: thach{at}kids.wustl.edu
Received 31 December 1997; accepted in final form 10 March 1999.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Different from adult and younger SWR mice
(P < 0.05, Bonferroni-Dunn
t-test).
