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Although periodic limb movements in sleep (PLMS) have been described in multiple pediatric publications, periodic limb movement disorder (PLMD) has not. The aims of this study were to describe the prevalence, sleep-related correlates, and polysomnographic correlates of PLMD in a large pediatric case series, and compare these to pediatric obstructive sleep apnea (OSA).All PLMD cases (defined by International Classification of Sleep Disorders, 2nd edition criteria + respiratory disturbance index [RDI]3) and OSA cases (defined by RDI ≥ 3 + PLMS5), from a single pediatric sleep practice, over a 2-year time span, were included. Chart, questionnaire, and polysomnographic data were compiled. Of 468 referred children, 66 PLMD cases were identified (14%).The PLMD cases, mean age 8.1 years (range 1-17), were clinically characterized by frequent sleep onset and maintenance problems, difficulty awakening, restless sleep, leg pain/discomfort at night, and parasomnias. Compared to 90 OSA children, those with PLMD had a history of significantly more sleep onset and maintenance problems, leg pain/discomfort at night, parasomnias, getting out of bed at night, and family history of restless legs syndrome. Polysomnographically, PLMD cases had more awakenings, stage 1 sleep, stage shifts, and spontaneous arousals.These data indicate that pediatric PLMD has important clinical and polysomnographic correlates. In addition, PLMD has many characteristics that are different from pediatric OSA, suggesting that PLMD is a distinct pediatric sleep disorder, of which clinicians should be aware.

Data from 249 children referred to a pediatric sleep clinic were analyzed. The first question of interest examined whether an International Classification of Sleep Disorders-Second Edition (ICSD-2)-based diagnosis of periodic limb movement disorder (PLMD) or sleep-disordered breathing (SDB) would more strongly associate with parental perceptions of daytime attention and behavior problems in their child. The second question was whether the outcome would differ based on PLMD diagnostic criteria-that is, previously used criteria to define PLMD (Periodic Limb Movement Index [PLMI]5 per hour vs. PLMIor= 5 per hour only) versus the ICSD-2 criteria. Parents of children with ICSD-2-defined PLMD perceived more problems with daytime behavior and attention, more symptoms of internalizing and externalizing, longer sleep latency, and more difficulty falling back to sleep than did parents of children with SDB. Most effects were lost when groups were defined by PLMI alone. The PLMI had acceptable sensitivity but low specificity in diagnosing PLMD.

Cigarette smoking and cocaine use in pregnancy are common in the US and both are risk factors for sudden infant death syndrome (SIDS). Although the cause of SIDS is not known, one postulated mechanism involves abnormalities of arousal and arousal regulation. Cigarette smoking and cocaine use may cause deficits of arousal. Many believe arousal deficits occur prenatally.The aim of this study was to assess the effects of cigarette smoke and cocaine exposure during pregnancy on measures of fetal arousal and arousal competency: 1) the fetal response to vibroacoustic stimulation (VAS) and 2) habituation to VAS.Maternal cigarette smoking and cocaine use in pregnancy are associated with altered arousal and arousal regulation in the fetus.Three groups of mother-fetal dyads were enrolled: 1) cigarette smokers (n = 54), 2) cocaine users (n = 30), and 3) controls (n = 60). One hundred eight fetuses were tested at 29-31 wk gestation, 119 at 32-35 wk, and 118 at 36+ wk. The fetal response to VAS was assessed using real-time ultrasound and a paradigm of arousal responsiveness. Responders were tested with repeated VAS to assess habituation. Also, the quality of fetal reactivity to repeated stimuli was assessed as a measure of arousal and arousal regulation competence (Behavioral Reactivity Scale).The control group had a larger proportion of fetuses who were too active to initiate testing ("too active to test") (p = 0.013); the proportion of fetuses too active to test decreased with increasing gestational age. The majority of the fetuses who could be tested responded to the initial VAS, and there were no group differences. The proportion of fetuses that habituated and the rate of habituation did not differ between the groups. Behavioral reactivity did not differ between groups.The original hypotheses were not confirmed. However, the chosen assessment paradigms may have lacked sensitivity. The proportion of fetuses that were "too active to test" decreased with gestational age. The control group had a larger proportion of fetuses that were "too active to test" compared with the exposure groups. We speculate that these findings indicate that prenatal exposure to these neuroteratogens may have produced an acceleration of the behavioral response to vibroacoustic stimulation.

The authors used the Fagan Test of Infant Intelligence (J. F. Fagan, L. T. Singer, J. E. Montie, & P. A. Shepherd, 1986) to examine preferences for novelty and to evaluate several indicators of attention (off- and on-task indexes and durations) in 6- and 9-month-old infants who had been prenatally exposed to cigarette smoke only or to cocaine plus other substances. The infants were matched for socioeconomic status. The authors found no group differences in preference for novelty, but the off-task distractibility index and duration were affected by exposure history and showed effects of dosage at the 9-month test time. Infants exposed to cocaine had a higher off-task index and a shorter average off-task look duration than did infants in the other groups. The authors interpreted this pattern of behavior as an indicator of distractibility or stimulation seeking. There were no group differences in measures involving on-task looks or duration at either test time. Correlations between the off-task look index and duration and teratogen use produced moderate correlations at 9 months of age. The authors calculated partial correlations between teratogen exposure and the off-task index at each trimester. Cocaine use during the 1st and 2nd trimesters was significantly correlated with the off-task index at 9 months of age, even when the authors controlled for neonatal measures (e.g., gestational age, birth weight) and during the 1st trimester when they controlled for alcohol and cigarette exposure.

Objective To examine the effects of maternal cigarette smoking during pregnancy on the developing infant's autonomic regulation before the possible effects of parturition and neonatal withdrawal could alter outcome measures. Methods Heart rate variability (HRV) was assessed for 10 min during late gestation for 21 cigarette-exposed (CE) and 22 nonexposed (NE) fetuses. Results HRV was significantly lower in fetuses whose mothers smoked cigarettes during pregnancy. Spectrum analysis of that variability showed temporally organized rhythms at a frequency similar to rhythms previously found in fetal cyclic motility (approximately .3 cycles per min). Lower powered rhythms--associated with poorer development--at the first, second, and dominant rhythms, as well as lower overall power of the power spectrum, were found for CE fetuses. Pearson correlations showed significant negative correlations between the amount of maternal cigarette smoking during the first trimester of pregnancy and measures of fetal HRV and power of spectral peaks. Conclusions Results show that CE fetuses have lower HRV and disrupted temporal organization of autonomic regulation before effects of parturition, postnatal adaptation, and possible nicotine withdrawal contributes to differences in infant neurobehavioral function.

Behavioral states are stable structures of behaviors that become more definable and coordinated with increasing age. With ultrasound we can see the fetus move, breathe, and react to changes in its environment. Ultrasound used in conjunction with Doppler fetal heart rate recording provides behavioral and neurophysiologic data useful in state determination. The Fetal Neurobehavioral Profile (FNP) was developed by our group as an assessment of fetal behaviors reflecting CNS integrity in the drug-exposed fetus. The FNP was designed to parallel methods of examining the newborn infant, especially in state-related behaviors. The FNP measures: fetal responsiveness and arousal after environmental perturbation with vibroacoustic stimulation (VAS); habituation to VAS; state recovery; and self-regulation post-VAS. From the behavioral and physiologic recordings, the constructs of state differentiation, organization, and regulation as well as fetal arousal and regulation competency can be measured. Previous work using the FNP showed that those fetuses with abnormal or suspect fetal state regulation demonstrated impaired performance on the NBAS (Am. J. Obstet. Gynecol. 161: 685, 1989). To expand these observations, three populations are currently being studied: prenatal nicotine-exposed, prenatal cocaine-exposed, and controls. Data are from 97 women/fetus dyads and a total of 236 FNP at ages 28-30 weeks gestational age, 31-34 weeks gestational age, and > 36 weeks gestational age. Although there are no group differences in the ability to achieve state by 36 weeks, interesting trends emerge: fetuses prenatally cocaine-exposed spend less time in 1F, more time in 4F and have fewer transitions. At FNP, fewer cocaine-exposed fetuses had an initial reaction to VAS, whereas fewer nicotine-exposed fetuses habituated. Although the ability to habituate to VAS did not discriminate the cocaine group from the control or nicotine groups, the number of stimuli required for habituation differed between groups: 7 for the cocaine-exposed, 3 for the nicotine, and 5 for the control groups. Thus latency, a measure of arousal, differs among the groups Preliminary data also suggest a correlation of prenatal data with postnatal outcome.

Prenatal cocaine or nicotine exposure is associated with a variety of teratogenic effects. The current study was conducted to determine their effects alone and in combination on cognitive function and sexual differentiation. Pregnant Long-Evans rats (N = 19) were exposed to either cocaine (15 mg/kg/dose b.i.d. SC on GD 8-20); nicotine (4 mg/kg/day continuous SC infusion on GD 4-20); both nicotine + cocaine; or vehicle only. Birth weight and anogenital distance (AGD) were measured in all pups at birth. Learning and memory were tested in the Morris water maze (MWM) during prepubertal and pubertal ages in five daily consecutive sessions and a sixth session 1 week later and in the radial-arm maze (RAM) during adulthood. In the RAM, a drug challenge of the beta-noradrenergic antagonist propranolol (10-20 mg/kg) was given after acquisition training. Maternal weight gain was reduced 13-42% and offspring birth weight was reduced by 7-12% in all three exposure groups compared to controls. Cocaine decreased the AGD of males (2.68 mm) compared to 2.88 mm in noncocaine-exposed male pups (p < 0.025). A sex-selective cocaine effect was also seen after adjustment of AGD measurements for body weight. With this measure cocaine-treated females showed significantly (p < 0.05) greater AGD than those not exposed to cocaine. In the MWM, there were two types of trials: cued reference memory trials and uncued spatial working memory trials. On cued reference memory trials significant cocaine-induced latency deficits were seen on only the first session. On spatial working memory trials cocaine-induced latency deficits were seen throughout daily training on sessions 1-5, but not the retention session 6, 1 week later. During RAM acquisition, there were no significant differences in choice accuracy between exposure groups. Following propranolol challenge, deficits in choice accuracy were demonstrated in rats prenatally exposed to cocaine or nicotine. These rats did not show any response to propranolol, whereas the controls slightly improved their choice accuracy. The results of this study indicated that prenatal cocaine exposure altered long-term cognitive function under basal conditions in the MWM and drug challenge in the RAM, birth weight, and genital development. Cocaine-induced cognitive deficits were predominately in working memory rather than reference memory or long-term retention. Prenatal nicotine exposure was only observed to alter birth weight and cognitive function in response to propranolol challenge in the RAM.

The project presented in this paper began in 1993. It consists primarily in a graphical user interface for the real-time simulator at IREQ. It is based on a single-line schematic display and it uses the paradigm of model-view-controller objects. The first phase of the project includes a schematic editor with all the functionality of a generic editor (color, zoom, connectivity, etc.) combined with the effective control of elements of the real-time simulator. The next phase will include support for three-phase representation and integration to the network database of the real-time simulator at IREQ. This work has permitted us to explore and master object concepts that will improve the development and evolution of graphical user interfaces at IREQ.

Twelve-hour overnight pneumocardiograms were assessed for sleep architecture and sleep efficiency in two groups of healthy term newborn infants: a group exposed prenatally to cocaine alone or in combination with other drugs and a non-exposed group. Sleep was differentiated from wakefulness by an increase in heart rate, an increase in or variation in the duration and amplitude of the respiration and increased artifacts on the heart rate channel. Quiet and active sleep were determined by the regularity or irregularity of heart rate and respiration. In a sub-set of infants, the number of arousals during active sleep was calculated. Overall significance was confirmed by ANOVA followed by paired comparisons using the Student's-test. When compared to non-exposed infants within the first week of life, infants exposed prenatally to cocaine alone or in combination with other drugs demonstrated more wakefulness and less steep (P < 0.05), more frequent arousals during active sleep (P < 0.01), and the tendency of a higher proportion of active sleep compared to quiet steep. These findings may have implications to both behavioral and respiratory control findings associated with prenatal cocaine exposure.

To examine the development of daily variations in dopamine levels, we measured dopamine concentrations within five distinct brainstem regions in 3- and 21-day-old, and adult rabbits at 09.30, 15.30, 21.30 and 03.30 h. Dopamine was measured by radioenzymatic assay and the dopamine concentration was expressed relative to wet tissue weight. In addition to defining the presence of a daily variation in the dopamine concentration in the whole brainstem, we were interested in identifying brainstem region-specific differences in this daily variation. Our data suggest that daily variations in dopamine concentrations are established by 3 days of life. Analysis of gross brainstem daily variation data suggest a peak in the dopamine concentration during the early light phase (09.30 h) for 3-day-old animals in contrast to a late light phase peak (15.30 h) for 21-day-old animals. Adult animals showed a peak in the early dark phase (21.30 h). These gross daily variations reflect the net sum of distinct region-specific patterns in the dopamine concentration. Analysis by region reflects a region-specific ontogeny in the development of daily variations for dopamine. Dopamine is involved in cardiorespiratory regulation. The observed developmental patterns may relate to the maturation and integration of these physiologic processes.

The AAP has alerted pediatricians to the importance of safe sleep environment for infants. The elements of a safe sleep environment include supine sleep position, safe crib, and avoidance of smoke exposure, soft bedding, and overheating. With the Back to Sleep campaign, prone sleeping among all U.S. infants has decreased to less than 20%, and the incidence of SIDS has decreased 40%. However, the decline in SIDS and prone sleeping has leveled off in recent years. Further declines may be possible with decreasing other modifiable risk factors, such as prenatal and postnatal exposure to cigarette smoking. Prior studies have demonstrated that health care professional advice is influential in determining infant care practices. It is important that physicians caring for infants be aware of the importance of a safe sleep environment and understand other modifiable risk factors for SIDS. We surveyed a random sample of 3,717 physicians in North Carolina and the metropolitan Washington, DC, area to determine knowledge, beliefs, and practices regarding SIDS and SIDS risk reduction among physicians caring for pregnant women and infants. Twenty-three percent (835) responded. Most physicians are aware of prone sleeping and cigarette smoke exposure as risk factors for SIDS. Almost all physicians agree that there are measures that can be taken to reduce the risk of SIDS, and they consider it important to discuss SIDS and SIDS risk reduction strategies with parents of young infants. In spite of this belief, only 56% of family/general practitioners, 18% of obstetrician-gynecologists, and 79% of pediatricians discuss SIDS routinely. Only 35% of pediatricians, 15% of family/general practitioners, and 16% of obstetrician-gynecologists provide written information. In addition, only 38% of physicians recommend supine, while 50% recommend side or back, 6% side, and 7% prone. Only two thirds of pediatricians and one third of family/general practitioners are aware that the AAP recommends supine as the preferred sleep position for infants. Pediatricians are more likely to be aware of the AAP recommendation (p

To test the hypothesis that respiratory control is altered in cocaine-exposed infants, we evaluated the hypoxic arousal response and the ventilatory response to carbon dioxide (CO2) in 18 term newborn infants prenatally exposed to cocaine and in 10 healthy, term newborn infants within the first week of life. Three infants could not be tested for the hypoxic arousal response because of low baseline oxygen saturation, and data from these infants were excluded from analysis. Twelve hour overnight pneumocardiograms were performed on all infants. Results show that 60% (9/15) of the prenatally cocaine-exposed infants had an abnormal hypoxic arousal response and 87% (13/15) had abnormal hypercarbic ventilatory response. Only 6% (1/15) of the prenatally cocaine-exposed infants demonstrated any abnormality on pneumocardiogram. In contrast, all control infants (10/10) were aroused by the hypoxic challenge and 80% (8/10) had normal ventilatory response to CO2. No abnormalities were found in the assessment of the overnight pneumocardiogram in the control infants. For the cocaine-exposed infants, test abnormalities were not correlated with a concurrent positive urine toxicology for cocaine, suggesting that the injury occurs early in development. These findings support the hypothesis that infants prenatally exposed to cocaine demonstrate abnormalities of respiratory control.

The dramatic increase in cocaine use over the past decade has led to a concern about its possible teratogenicity. We have identified 6 structural fetal anomalies which we postulate may have cocaine-induced vascular accidents as the teratogenic mechanism: 2 complex choroid plexus cysts, gastroschisis, meconium peritonitis, urethral stenosis, and radial hypoplasia. Two additional anomalous neonates were born to perinatal cocaine users. Eight of 51 (15.7%) cocaine-exposed perinates exhibited anomalies versus 120 of 2,194 (5.4%) perinates without known cocaine exposure during this time period. This represents a 3-fold relative risk (RR = 2.87, OR = 3.22, chi square = 9.68, p0.005) for the cocaine-exposed fetus. Subjects were all identified as cocaine users prior to ultrasound-detected anomaly and ultrasonologists were blinded to maternal drug history. The vascular disruption model as the plausible mechanism for cocaine-associated teratogenesis is supported by the type of anomalies reported. In addition, cocaine use was prospectively determined to have occurred at the critical developmental period in each case.

Ornithine decarboxylase, a modulator of tissue growth during fetal and neonatal mammalian development, serves as a sensitive marker enzyme for perturbations in neural development. To test the hypothesis that cocaine is a central nervous system neurodevelopmental teratogen through mechanisms involving direct cellular injury, we measured ornithine decarboxylase activity in brain sections of 4- to 6-day-old rabbit pups which were prenatally cocaine exposed and in pair-fed and free-fed controls. Rabbit does were implanted with the osmotic minipump prior to Gestational Day 10 and cocaine and/or sterile water was delivered between Gestational Days 10 and 32. The flow rate in the cocaine group was calculated to provide a daily cocaine dose of 30 mg/kg/day. Pups were sacrificed, brains were dissected into the cortex, pons, and medulla, and ornithine decarboxylase activity was measured. When compared to the pair-fed group, prenatal cocaine exposure significantly decreased ornithine decarboxylase activity in the cortex (0.531 ± 0.070 nmol/g/h SEM vs 0.913 ± 0.201 nmol/g/h SEM; cocaine vs pair fed, respectively; P ≤ 0.05) and in the pons (0.533 ± 0.036 nmol/g/h SEM vs 0.728 ± 0.075 nmol/g/h SEM, cocaine vs pair fed, respectively; P ≤ 0.05) but not in the medulla (0.374 ± 0.040 nmol/g/h SEM vs 0.392 ± 0.045 nmol/g/h SEM, cocaine vs pair fed, respectively; P > 0.05). Although there were no statistically significant differences in ornithine decarboxylase activity between the cocaine-exposed group and the free-fed group in any brain region, all regions showed a relative decrease in ornithine decarboxylase activity with prenatal cocaine exposure. These data support the concept that prenatal cocaine exposure and malnutrition play a role in the adverse central nervous system outcomes associated with prenatal cocaine exposure.

As cocaine use during pregnancy has become increasingly recognized, there also has been increased concern about the toxic and teratogenic properties of cocaine on the fetus. A significant literature exists describing the adverse fetal and neonatal outcomes associated with in utero cocaine exposure. However, specific causality by cocaine on outcome in the human is difficult to ascertain because of multiple confounding variables associated with substance abuse including social factors and polydrug use as well as difficulty in confirming timing, dose and frequency of cocaine exposure. Most literature suggests that prenatal cocaine exposure is associated with developmental risk to the fetus. What is currently unknown is the extent of risk, the additive and/or synergistic factors contributing to cocaine's toxicity and the reversibility of the injury. In this paper we review the pharmacologic properties of cocaine as related to a model of mechanisms for developmental injury secondary to cocaine exposure and the published literature on the adverse fetal and neonatal outcomes associated with cocaine use during pregnancy. Specific attention has been focused on the structural, neurobehavioral and respiratory control teratogenesis.

Recently, investigators have reported an alteration of postnatal respiratory pattern, deficient hypoxic arousal from sleep, and an increased incidence of sudden infant death syndrome (SIDS) among human infants exposed to cocaine prenatally, thus suggesting that prenatal cocaine exposure may perturb the maturation of respiratory control thereby increasing the risk for SIDS. To investigate the effects of prenatal cocaine on postnatal respiration, we evaluated the ventilatory response to 0.21 FIO2 (baseline) and at 0.15, 0.10, and 0.08 FIO2 by the barometric method on days 4-5 of life in 23 New Zealand White rabbit pups born to cocaine-exposed (30 mg/kg/day of cocaine HCl by continuous subcutaneous infusion), pair-fed and free-fed does. The chamber pressure deflection (proportional to VT after appropriate calculation) was computer-sampled at 200 Hz when the unanesthetized pups were resting quietly with no gross body movements. Recording was made after 10 min acclimatization to a specific FIO2. We found that baseline ventilation did not differ significantly among study groups. However, minute ventilation (VI), inspiratory flow (VT/TI), tidal volume (VT), increased significantly with hypoxia to peak values at 0.08 FIO2 in pair-fed and free-fed pups but these measurements did not increase significantly in cocaine-exposed pups. Our finding of a deficient second phase of the hypoxic ventilatory response among cocaine-exposed pups supports the hypothesis that prenatal cocaine perturbs the maturation of respiratory control.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal cocaine (CC) exposure may result in increased fetal loss, growth retardation, altered neurodevelopment, and sudden infant death syndrome (SIDS). We sought to establish an animal model for prenatal cocaine exposure which (1) would allow us to distinguish the direct effects from the indirect and nutritional effects of the drug, and (2) might be used to address questions of cocaine's toxicity, specifically to the developing respiratory control system. The study design included 38 New Zealand White rabbit does among CC, pair-fed (PF), and free-fed (FF) groups. Miniosmotic pumps were implanted in each doe on day 10 of timed gestation providing continuous subcutaneous administration of either 30 mg/kg/day of cocaine HCl in H2O (CC) or sterile H2O alone (PF and FF). Mean (SEM) plasma cocaine concentration was 1.71 +/- 0.21 mumol/l (519.4 +/- 64.4 ng/ml). Pregnancy outcome compared for incidence of stillbirth, maternal death, spontaneous abortion, and gross malformation among 211 pups was significant only for increased stillbirths among CC pups (18%, p less than 0.04) as compared to PF (6%) and FF pups (7%). External and renal malformation and postnatal weight, crown-rump length, and snout-occiput head circumference for pups aged 4 and 5 days of age did not differ among groups. The direct effects of prenatal cocaine evaluated in our model do not reproduce the altered perinatal outcome observed among humans. However, our results do not determine if physiologic function has been altered. Investigation of the physiologic and pathologic abnormalities that are relevant to this human condition, specifically to the developing respiratory control system, should add clarity to the mechanism of action of cocaine during pregnancy.

Sophisticated radiotherapy techniques lead to more conformal dose distributions but increase treatment complexity. Image guidance allows for varying degrees of accuracy in patient set-up. However, the consequences of inaccurate set-up and/or patient motion during treatment become more serious when treatment doses are increased and treatment margins are decreased. Thus, the need to know if the dose has been delivered as planned has driven the development of plastic scintillation detector systems for accurate measurements in real time with high spatial resolution. We have developed a clinical prototype comprising 29 scintillating fiber detectors 1 mm in diameter and 2 mm in length. The detectors are coupled to clear optical fibers that collect the scintillation photons and transport them to a CCD for detection. Open field profiles and depth-dose profiles in water-equivalent phantoms were compared to ionization chamber measurements in water. The maximum relative in-field difference was 1.6%. With a standard deviation for in-field measurements smaller than 1%, this prototype array was found to be accurate, precise and practical. Monte Carlo simulations were also used to evaluate the response of the scintillation detector to proton beams and to optimize the light collection efficiency. The Monte Carlo code Geant4 was used to simulate dose deposition, the production of scintillation photons and the propagation of those photons inside the scintillation detector. Further development of the system will allow thousands of measurement points distributed in a three-dimensional volume per single irradiation, therefore producing a rapid evaluation of complex dose distributions emanating from these new complex treatment modalities.

Abnormalities of respiratory regulation, such as apnea and abnormal hypoxic arousal during sleep, are mechanistic in the pathophysiology of SIDS. In utero cocaine exposure is associated with poor head growth, abnormal neurodevelopment, and an increased incidence of sudden, unexplained death, suggesting that in utero cocaine exposure disrupts the central regulation of breathing. It is likely that this disruption is due to altered CNS maturation. Indeed, cocaine alters norepinephrine metabolism within the locus coeruleus, important in arousal from sleep, suggesting that the increased incidence of SIDS in cocaine exposed infants may be secondary to sleep-related deficits in arousal. Since components of fetal behavioural state organization reflect the successful integration of the Central Nervous System, have a specific developmental timetable, and can be studied by fetal ultrasound techniques, we developed a strategy for assessing the state organization of the fetus by ultrasound techniques. We hypothesize that fetal evaluation of state will be a marker of abnormal CNS maturation and a predictor of risk, i.e. abnormal neurodevelopent and/or state related arousal deficits predisposing the cocaine exposed neonate to SIDS. We propose that the study of in utero cocaine exposed fetuses will provide a human model for examining the pathophysiology of SIDS.

Respiratory control abnormalities are mechanistic in Sudden Infant Death Syndrome (SIDS). In particular, arousal from sleep is an important component of respiratory regulation. Cocaine alters central neurotransmitter metabolism, particularly the monoamines. The locus coeruleus, the major Norepinephrine (NE) neuronal system, is involved in arousal from sleep related apnea and has extensive forebrain and brainstem projections. Thus, it is plausible that in utero cocaine exposure disrupts the normal maturation of transmitters and/or brain structures essential to sleep related respiratory regulation. Infants exposed to cocaine in utero may have an increased incidence of SIDS. We propose that cocaine use in pregnancy alters the normal maturation of centers and/or neurotransmitters involved in respiratory regulation thereby altering postnatal respiratory control. We hypothesize that the increased incidence of SIDS in cocaine exposed infants may be secondary to deficits in arousal. The study of prenatal brain development and of postnatal respiratory control in rabbit pups exposed to cocaine in utero will provide a useful model for the study of mechanisms operative in SIDS.

To examine the development of daily rhythms in serotonin levels, we measured serotonin concentration within five distinct brainstem regions in 3-day-old, 21-day-old and adult rabbits at 09.30, 15.30, 21.30 and 03.30. Serotonin was measured by radioenzymatic assay in the superior and inferior colliculi, rostral pons, caudal pons and medulla, and serotonin concentration was expressed relative to wet tissue weight. In addition to defining the presence of a daily rhythm in serotonin concentration in whole brainstem, we were interested in identifying brainstem region-specific differences in this rhythm. Our data suggest that daily rhythms for serotonin are established by 3 days of life. Analysis of gross brainstem rhythm data suggests a nocturnal peak in serotonin concentration in 3-day-old and adult animals in contrast to a diurnal peak for 21-day-old animals. These gross rhythms reflect the net sum of distinct region-specific patterns in serotonin concentration. Analysis by region reflects a region-specific ontogeny in the development of daily rhythms in serotonin concentration. Serotonin is involved in the initiation of sleep. The observed developmental patterns may relate to the maturation and integration of sleep/wake states.

Four behavioural states are recognised in the human fetus and are comparable to those of the neonate: 1F (quiet sleep), 2F (active state), 3F (quiet awake), and 4F (active awake). State 5, or crying, is not considered to have a fetal correlate. In a study assessing the effects of exposure to tobacco and cocaine during pregnancy on fetal response and habituation to vibroacoustic stimulation, what appears to be the fetal homologue of crying was observed. These behaviours were seen on ultrasound, and have been captured on video recordings and include: an initial exhalation movement associated with mouth opening and tongue depression, followed by a series of three augmented breaths, the last breath ending in an inspiratory pause followed by an expiration and settling. This is the first report/video documenting these behaviours and suggests the possibility of a state 5F.

Simultaneous measurement of both neutrons and charged particles emitted in the reaction {sup 64}Zn + {sup 64}Zn at 45 MeV/nucleon allows comparison of the neutron to proton ratio at midrapidity with that at projectile rapidity. The evolution of N/Z in both rapidity regimes with increasing centrality is examined. For the completely reconstructed midrapidity material one finds that the neutron to proton ratio is above that of the overall {sup 64}Zn + {sup 64}Zn system. In contrast, the reconstructed ratio for the quasiprojectile is below that of the overall system. This difference provides the most complete evidence to date of neutron enrichment of midrapidity nuclear matter at the expense of the quasiprojectile.

The purpose of this study was to compare the relative strength of association between symptoms of attention deficit/hyperactivity disorder (ADHD) with sleep disordered breathing (SDB), periodic limb movement disorder (PLMD), and bedtime resistance behaviors (BRBs). The Pediatric Sleep Questionnaire was completed by parents of 283 children. Scales were derived to indicate risk for specific sleep disorders, then correlated with symptoms of ADHD. Strong independent interrelationships between symptoms of PLMD and symptoms of ADHD emerged, with potential additional contributions by bedtime resistance. These interrelationships remained after controlling for age, SDB, sleepiness, or BRBs. These data suggest ADHD symptoms may be especially related to PLMD but that insufficient sleep duration secondary to bedtime resistance and noncompliance may make an independent contribution.

Background Correlations between infant measures of information processing and later IQ have been established, and a few studies have extended this continuum by examining links between various fetal measures and cognitive measures during infancy. Aims This study compared fetal rate of behavioral habituation among infants identified as at high or low cognitive risk. Study design This study was a retrospective examination of differences in fetal rate of behavioral habituation as a function of cognitive risk status at 6.5 and 9 months postpartum, using an independent two-group design. Subjects Participants were 32 infants who were born between 36 and 42 weeks gestational age at normal birth weight and had normal APGAR scores. Outcome measures The Fagan Test of Infant Intelligence (FTII) was used to obtain a measure of preference for novelty, which served as the basis for identification of infants at high or low risk for cognitive difficulty. These infants had undergone up to three habituation trials using a vibroacoustic stimulus during fetal development. Results Infants who were classified as being at high cognitive risk at 6 months had required more trials to habituation as fetuses. Conclusions Fetal rate of behavioral habituation is associated with information processing during the first 6 months of infancy. We suggest that fetal habituation may be influenced by early cognitive mechanisms and therefore represents an immature but real form of information processing.

iwm2001

XL Bormio

Behavioral states are stable structures of behaviors that become more definable and coordinated with increasing age. With ultrasound we can see the fetus move, breathe, and react to changes in its environment. Ultrasound used in conjunction with Doppler fetal heart rate recording provides behavioral and neurophysiologic data useful in state determination. The Fetal Neurobehavioral Profile (FNP) was developed by our group as an assessment of fetal behaviors reflecting CNS integrity in the drug-exposed fetus. The FNP was designed to parallel methods of examining the newborn infant, especially in state-related behaviors. The FNP measures: fetal responsiveness and arousal after environmental perturbation with vibroacoustic stimulation (VAS); habituation to VAS; state recovery; and self-regulation post-VAS. From the behavioral and physiologic recordings, the constructs of state differentiation, organization, and regulation as well as fetal arousal and regulation competency can be measured. Previous work using the FNP showed that those fetuses with abnormal or suspect fetal state regulation demonstrated impaired performance on the NBAS (Am. J. Obstet. Gynecol. 161: 685, 1989). To expand these observations, three populations are currently being studied: prenatal nicotine-exposed, prenatal cocaine-exposed, and controls. Data are from 97 women/fetus dyads and a total of 236 FNP at ages 28-30 weeks gestational age, 31-34 weeks gestational age, and36 weeks gestational age. Although there are no group differences in the ability to achieve state by 36 weeks, interesting trends emerge: fetuses prenatally cocaine-exposed spend less time in 1F, more time in 4F and have fewer transitions. At FNP, fewer cocaine-exposed fetuses had an initial reaction to VAS, whereas fewer nicotine-exposed fetuses habituated. Although the ability to habituate to VAS did not discriminate the cocaine group from the control or nicotine groups, the number of stimuli required for habituation differed between groups: 7 for the cocaine-exposed, 3 for the nicotine, and 5 for the control groups. Thus latency, a measure of arousal, differs among the groups Preliminary data also suggest a correlation of prenatal data with postnatal outcome.

For 50 MeV/nucleon {sup 129}Xe+{sup nat}Sn multifragmentation events, we deduced, by means of correlation techniques, the multiplicities of the hydrogen and helium isotopes which were emitted by the hot primary excited fragments produced at the stage of the disassembly of an equilibrated hot source. We also derived the relative kinetic energy distributions between the primary clusters and the light charged particles that they evaporate. From the comparison between the secondary multiplicities observed experimentally and the multiplicities predicted by the GEMINI model, we concluded that the source breaks into primary fragments which are characterized by the same N/Z ratio as the combined system. Knowing the secondary light charged particle multiplicities and kinetic energies, we reconstructed the average charges of the hot fragments and we estimated their mean excitation energies. The fragment excitation energies are equal to 3.0 MeV/nucleon for the full range of intermediate mass fragment atomic number. This global constancy indicates that, on the average, thermodynamical equilibrium was achieved at the disassembly stage of the source. {copyright} {ital 1998} {ital The American Physical Society}

We present a novel, high-resolution 3D dosimeter based on the tomographic acquisition of the dose using long scintillating fibers. This study aims to demonstrate the concept of the dosimeter with simulated acquisitions using the input dose from Pinnacle3. The dosimeter is composed of concentric, cylindrical planes in which scintillating fibers are placed at different angles between the fiber and the cylindrical plane. Upon a complete rotation of the device around its central axis, the incident dose distribution on the cylindrical planes can be reconstructed using tomographic reconstruction algorithm. The 3D dose in the dosimeter can then be interpolated from the cylindrical 2D dose distributions. Using a simulated acquisition composed of two concentric cylindrical planes of 36 and 32 fibers each, we achieve below 1% local dose difference between the reconstructed 3D dose and the expected dose from Pinnacle3 in the high dose, low gradient region of the volume encompassed inside the innermost cylindrical plane. The results show the potential of the method to perform high-resolution 3D dose measurements of both square and IMRT fields.

Purpose: To use a simple deformable image registration (DIR) scheme to correct CBCT images in order to use them for treatment plan assessment and replanning. Methods: A dataset of five prostate patients with weekly CBCT scans was available for this study. Contours of soft‐tissue organs were made on the planning CT as well as on each CBCT. The following procedure was applied: (1) a mask was automatically generated to exclude certain area from the registration (table couch, CBCT truncated region due to limited field of view); (2) a B‐spline based DIR algorithm was used to register each plan CT to daily CBCTs; (3) CBCT regions where air appeared (i.e. air is seen on the CBCT but not on the plan CT) were automatically segmented and excluded from the registration because of the poor performance of DIR algorithms in such cases. Results: Prior to DIR, the average differences in Houndsfield units between CT and CBCT were 26, 7, 107, 125 for the prostate, bladder, seminal vesicles and rectum respectively. After DIR these differences were respectively reduced to 5, 5, 4, 2. The external contours of the patients were assessed using Dice's coefficient. On average the Dice coefficient between CT and weekly CBCTs was 0.92. After DIR this value was improved to 0.97. Furthermore by registering the larger CT to shorter CBCT (i.e. 64 slices only) we obtain realistic scattering media outside the immediate CBCT field of view. The whole process takes about 4 minutes although no explicit speed optimization has been done yet. Conclusion: This technique has several advantages for plan assessment and/or replanning purposes: it combines the accurate Houndsfield numbers from the plan CT with the daily anatomy of the CBCT, preserve the external contour and provide realistic scattering media outside the CBCT field of view.

To examine the development of daily variations in norepinephrine levels, norepinephrine concentrations were measured within five distinct brainstem regions in 3-day-old, 21-day-old, and adult rabbits at 6-h intervals throughout the day. Norepinephrine was measured by radioenzymatic assay, and norepinephrine concentration was expressed relative to wet tissue weight. The data suggest that daily variations for norepinephrine concentrations are established by the third day of life. In the brainstem as a whole, there was an early nocturnal peak (2130 hours) for 3-day-old animals in contrast to a late nocturnal peak (0330 hours) for 21-day-old animals. Adult animals showed a late diurnal (1530 hours) peak. These gross daily variations constitute the sum of distinct region-specific patterns in the development of daily variations in norepinephrine concentration. Norepinephrine is involved in cardiorespiratory regulation and in the regulation of sleep/wake cycles. The observed developmental patterns may relate to the maturation and integration of these physiologic processes.

Purpose: To ensure the quality assurance of small field, dynamic radiotherapy, we present and validate a radiation tracking system based on long scintillating fibers that allows for the real‐time measurement of the position and energetic fluence of a small incident radiation field. Method: We aligned 60 parallel scintillating fibers on a thin grooved acrylic slab with a 100‐cm source‐to‐fibers distance. Both ends of each scintillating fiber were coupled to clear optical fibers to enable light collection by a single CCDcamera using an f/0.95, 50 mm focal length lens. Using a small, static photon radiation field of 2×2 cm2 of a Varian Clinac iX, we changed the interaction position on the prototype using the linac treatment couch. The interaction position parallel and perpendicular to the scintillating fiber array were deduced using the optical attenuation of the scintillating fibers. The energetic fluence of the incident field was calculated from the fibers light fluxes, corrected for the position dependent optical attenuation and scintillation efficiency. Results: Considering a treatment couch positioning error of ±0.5 mm, the system was able to measure the field position with a mean error of 0.1 mm perpendicular and 0.8 mm parallel to the scintillating fiber array. The maximum error measured using this setup was of 0.13 mm perpendicular and 3.2 mm parallel to the scintillating fiber array. The energetic fluence was determined with a mean error of 0.5% and a maximum error of 2.2%. Conclusions: This work demonstrates the capacity of a long scintillating fibers array to detect in real‐time both the position and the energetic fluence of an incident small radiation field. Such methodology would allow for the real‐time tracking of small field in both photon and particle radiation therapy.

Purpose: To assess treatment plan selection in a multiple plans adaptive IGRT strategy in routine clinical workflow. Methods: Continuous Offline Replanning (COR) is an adaptive IGRTtreatment strategy where patient treatment plan is selected from a pool of offline previously calculated plans based on the patient repositioning CBCTimages. A treatmentsequence with n=19 fractions was simulated and, with COR strategy, different selection approaches based on numerical analysis of DVH extracted values (COR_PTVV95, COR_CF) or on qualitative human selection (COR_H) were investigated. In numerical analysis, PTV coverage and multi‐objectives cost function were investigated. Each COR strategy was compared with the standard IGRT strategy using prostate center of mass translations (IGRT_0), and an optimal online replanning strategy (IGRT_Opt). In COR_H, operators were asked to select the most appropriate plan available from a screen display, priorizing geometrical fit of prostate, rectum and bladder contours on CBCTimages. Results: Cumulative average values of PTV V95 range from 92.9 to 95.5% for COR_H; 93.2 to 97.7 % for COR_PTVV95; 92.7 to 93.2% for IGRT_0 and 99.9 to 100% for IGRT_Opt, which ranks IGRT_Opt as the best treatment option and the COR_PTVV95 as second best option. Values of the multi‐objectives cost function were consistent with PTV coverage and were in the range 0.71 to 2.62; 0.36 to 2.40; 1.74 to 2.69 and 0.014 to 0.021 respectively for COR_H, COR_CF, IGRT_0 and IGRT_Opt. Operators were asked to choose preferentially among the first 10 contour sets to see if 10 plans were sufficient to represent the diversity of anatomical configurations routinely seen. They succeeded for 17/19 fractions. Conclusions: For multiple plans adaptive prostate IGRTtreatment, numerical selection process of daily plan based on target dose coverage or cost function values appear to be superior to human visual selection. Further development aim to minimize time selection procedure. Part of this work was financially supported by Varian Medical Sytems France.

Purpose: To present an original adaptive radiation therapy technique using daily CBCTimages.Method and Materials: For each fraction (fx) of a prostate treatment of 76Gy (n=38 fx), daily kV CBCT dataset was used for: (1) patient repositioning based on prostate soft tissue manual match; (2) generating an optimized 7‐beam IMRT plan which was also calculated on every subsequent fx. This allows building a pool of plans containing numerous anatomical configurations considering bladder and rectum fillings and relative positions. Three strategies were elaborated: (1) “classical strategy”, a non‐correction strategy where the patient is entirely treated with the initial CT‐based plan; (2) “optimal strategy”, an online strategy where the patient is treated with the daily optimized CBCT‐based plan; (3) “Continuous Offline Replanning” (COR) strategy, uses a pool of calculated offline plans from previous fx CBCT sets. The patient is treated with the “best” available plan satisfying volumetric and dosimetric indices. Results: A total of 741, n(n‐1)/2, plans were calculated. With the classical strategy, for 14/38 fractions, PTV dose coverage V(95%) ranged from 94.83% to 100%. Unsurprisingly, dose coverage was excellent in the “optimal strategy” with an average of 99.95% for the 38 fractions. In the COR strategy, dose coverage ranged from 95.31% to 100% for 35/38 fractions which represents a significant treatment enhancement compared with the classical strategy. A subset of only 8 plans was enough to achieve this result with COR. Conclusion: This study opens a novel and efficient offline approach to replanning using daily CBCTimaging.

Recently, investigators have reported an alteration of postnatal respiratory pattern, deficient hypoxic arousal from sleep, and an increased incidence of sudden infant death syndrome (SIDS) among human infants exposed to cocaine prenatally, thus suggesting that prenatal cocaine exposure may perturb the maturation of respiratory control thereby increasing the risk for SIDS. To investigate the effects of prenatal cocaine on postnatal respiration, we evaluated the ventilatory response to 0.21 FIO2 (baseline) and at 0.15, 0.10, and 0.08 FIO2 by the barometric method on days 4-5 of life in 23 New Zealand White rabbit pups born to cocaine-exposed (30 mg/kg/day of cocaine HCl by continuous subcutaneous infusion), pair-fed and free-fed does. The chamber pressure deflection (proportional to VT after appropriate calculation) was computer-sampled at 200 Hz when the unanesthetized pups were resting quietly with no gross body movements. Recording was made after 10 min acclimatization to a specific FIO2. We found that baseline ventilation did not differ significantly among study groups. However, minute ventilation (VI), inspiratory flow (VT/TI), tidal volume (VT), increased significantly with hypoxia to peak values at 0.08 FIO2 in pair-fed and free-fed pups but these measurements did not increase significantly in cocaine-exposed pups. Our finding of a deficient second phase of the hypoxic ventilatory response among cocaine-exposed pups supports the hypothesis that prenatal cocaine perturbs the maturation of respiratory control.(ABSTRACT TRUNCATED AT 250 WORDS)

We have reported a case of neonatal Torulopsis glabrata peritonitis and ventriculitis associated with a ventriculoperitoneal shunt. Treatment of fungemia and ventriculitis with amphotericin B and 5-fluorocytosine was successful.

Nicotine and/or Cocaine Alters Postnatal Ventilatory Control in the Rat Pup Gestationally Exposed

Maternal Cigarette-Smoking and Cocaine/Polydrug Use during Pregnancy: Comparable Disruptive Effects on Fetal Autonomic Regulation

Development of the Hypoxic Arousal Response in Healthy Infants: Impact of Maternal Cigarette Smoking and Cocaine Use during Pregnancy

In our Infant Care Project we integrate prenatal, substance abuse, and child services for pregnant women who are abusing drugs and their children. Three groups are identified to study the intervention and the relative contributions of biological and environmental factors: women recruited prenatally (early intervention), those identified postnatally (late), and a matched comparison group with no known drug use.

Components of fetal behavioral state organization reflect the successful integration of the central nervous system, have a specific developmental timetable, and can be studied with fetal ultrasonographic techniques. To test the hypothesis that evaluation of state organization is a marker of abnormal central nervous system maturation and a predictor of risk, we studied 20 fetuses and newborns exposed to cocaine in utero. Fetal assessments were accomplished by serial ultrasonographic examination, videotaped, and scored by a scheme developed by the authors to assess organization and regulation of behavioral states. Newborn neurobehavioral assessments also emphasized organization and regulation of behavioral state. Abnormal or delayed state behavior was identified in 13 of 20 fetuses. State organization was evaluated as suspect or abnormal for 16 of the 20 exposed newborns. Disorganized behavioral state in the fetus successfully predicted abnormal newborn behavior. These findings support the concepts that cocaine exposure disrupts central nervous system development and that fetal assessment of state is predictive of neonatal outcome.