Mary Anne F. Epstein

Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate.

: A new congenital syndrome characterized by the simultaneous failure of control of ventilation (Ondines curse) and intestinal motility (Hirschsprungs disease) is reported in three infants, all of whom died in the first few months of life; two were siblings. Detailed studies in one also revealed markedly decreased esophageal motility and abnormal control of heart rate. In one infant, minute ventilation was lower in quiet than in REM sleep and lower in both states of sleep than in wakefulness. Although the mean inspiratory flow was decreased in quiet sleep, the hypoventilation resulted primarily from a decrease in respiratory frequency. Intravenous doxapram increased ventilation but did not reverse respiratory failure. Aminophyllin, progesterone, physostigmine and chlorpromazine did not change ventilation significantly; imipramine resulted in a significant decrease. Both long and short-term variability of the heart rate were markedly decreased when compared with the normal infant. Although neuropathologic studies postmorten did not reveal an anatomic defect, we postulate that a developmental abnormality in serotonergic neurons is responsible for this new syndrome.

Fluid Flow Induction of Cyclo-Oxygenase 2 Gene Expression in Osteoblasts Is Dependent on an Extracellular Signal-Regulated Kinase Signaling Pathway†‡

Mechanical loading of bone may be transmitted to osteocytes and osteoblasts via shear stresses at cell surfaces generated by the flow of interstitial fluid. The stimulated production of prostaglandins, which mediates some effects of mechanical loading on bone, is dependent on inducible cyclo‐oxygenase 2 (COX‐2) in bone cells. We examined the fluid shear stress (FSS) induction of COX‐2 gene expression in immortalized MC3T3‐E1 osteoblastic cells stably transfected with −371/+70 base pairs (bp) of the COX‐2 5′‐flanking DNA (Pluc371) and in primary osteoblasts (POBs) from calvaria of mice transgenic for Pluc371. Cells were plated on collagen‐coated glass slides and subjected to steady laminar FSS in a parallel plate flow chamber. FSS, from 0.14 to10 dynes/cm2, induced COX‐2 messenger RNA (mRNA) and protein. FSS (10 dynes/cm2) induced COX‐2 mRNA within 30 minutes, with peak effects at 4 h in MC3T3‐E1 cells and at ≥8 h in POBs. An inhibitor of new protein synthesis puromycin blocked the peak induction of COX‐2 mRNA by FSS. COX‐2 promoter activity, measured as luciferase activity, correlated with COX‐2 mRNA expression in both MC3T3‐E1 and POB cells. FSS induced phosphorylation of extracellular signal‐regulated kinase (ERK) in MC3T3‐E1 cells, with peak effects at 5 minutes. Inhibiting ERK phosphorylation with the specific inhibitor PD98059 inhibited FSS induction of COX‐2 mRNA by 55‐70% and FSS stimulation of luciferase activity by ≥80% in both MC3T3‐E1 and POB cells. We conclude that FSS transcriptionally induces COX‐2 gene expression in osteoblasts, that the maximum induction requires new protein synthesis, and that induction occurs largely via an ERK signaling pathway.

Fluid flow induces COX-2 expression in MC3T3-E1 osteoblasts via a PKA signaling pathway.

Mechanical loading of bone generates fluid flow within the mineralized matrix which can exert fluid shear stress (FSS) at cell membranes. FSS induces new transcription of cyclooxygenase-2 (COX-2) in MC3T3-E1 osteoblasts, with peak effects at 4-5h. Using MC3T3-E1 cells stably transfected with the COX-2 promoter fused to a luciferase reporter, we examined involvement of the protein kinase A (PKA) and protein kinase C (PKC) signaling pathways in the peak COX-2 mRNA and luciferase responses to FSS (10dyn/cm(2)). Neither inhibition nor down-regulation of the PKC pathway affected the FSS stimulation of COX-2 mRNA or luciferase activity. In contrast, inhibitors of the PKA pathway, used at doses which inhibited forskolin-stimulated luciferase activity by 70-80%, reduced FSS-stimulated COX-2 mRNA expression and luciferase activity by 50-80%. Hence, peak FSS induction of COX-2 expression in MC3T3-E1 osteoblastic cells is largely dependent on the PKA signaling pathway.

Heart rate and heart rate variability during sleep in aborted sudden infant death syndrome

Heart rate and heart rate variability were studied during sleep at monthly intervals in 18 normal infants and 12 infants with aborted sudden infant death syndrome during the first four months of life. At each age studied and in both REM and quiet sleep, the aborted SIDS infants had a 5 to 10% faster heart rate. Moreover, the aborted SIDS infants had a 10 to 45% smaller beat-to-beat and overall heart rate variability. Although the differences in overall variability persisted after normalization by the absolute heart rate, the differences in the beat-to-beat variability narrowed. These findings, when taken in conjunction with our previous observation that aborted SIDS infants have a smaller QT index than normal infants, suggest that infants with aborted SIDS have an increase in sympathetic activity or in circulating levels of catecholamines.

The QT interval in aborted sudden infant death syndrome infants.

Summary: The QT interval was measured in 12 normal and 7 aborted sudden infant death syndrome (SIDS) infants in rapid eye movement (REM) and quiet sleep at monthly intervals through the age of 4 months. An accuracy of better than 2 msec was assured by high resolution of the digitized signal and calibration of each QT measurement with an accurately generated time code. In contrast to current speculations, the QT index was significantly smaller in the infants with aborted SIDS than in the normal infants in both REM and quiet sleep (P < 0.05). In addition, as in normal infants, the QTC was smaller in REM than in quiet sleep (P < 0.01). Although these results offer no support for the hypothesis that SIDS results from prolongation of the QT interval, they suggest that aborted SIDS infants have a functional abnormality in the autonomic nervous system.Speculation: We suggest that 1) the shortening of the QT interval in the aborted SIDS infants results from a uniform increase in the sympathetic outflow to the cardiac ventricles or an increase in circulating levels of catecholamines; and 2) an imbalance between the left and the right sympathetic outflow to the ventricles of aborted SIDS infants, as has been previously hypothesized, is not likely since the QTc was not larger in REM sleep, a sleep state in which an increase in sympathetic activity occurs.

Relation of Beat-to-Beat Variability to Heart Rate in Normal Sleeping Infants

Summary: The relationship of beat-to-beat heart rate variability (delta RR) and instantaneous heart rate was studied in eight normal infants while asleep during the first four months of life. The sleep state (REM or quiet) was determined using neurophysiologic and behavioral criteria. The results of regression analyses indicated that the delta RR values were positively correlated with the instantaneous heart rate (RR intervals). The correlation coefficient range was 0.49 to 0.92 in quiet sleep and 0.50 to 0.93 in REM sleep. Regression analyses supported a linear approximation of the delta RR to RR relation over the RR range investigated (400 to 520 msec). The median slope was 0.124 in REM and 0.117 in quiet sleep. The slopes of these linear functions were similar in both sleep states and at all ages. If beat-to-beat variability is to be used as an index of the integrity of the autonomic nervous system, these results suggest that delta RR be corrected for RR. A model is presented which relates the demonstrated positive correlation of delta RR to RR with the physiology of cardiac output control.Speculation: The positive correlation of delta RR with RR is consistent with the view that beat-to-beat heart rate variability is a homeostatic mechanism required for control of cardiac output.

Soda lime adsorption of isoflurane and enflurane.

The authors demonstrated that soda lime will adsorb enflurane or isoflurane as a function of the water content of the soda lime. Various volumes of liquid enflurane or isoflurane were placed in an equilibration flask containing fresh (15% water by weight) or dried soda lime and the vapor phase anesthetic concentrations plotted. When dry soda lime was used, the plot of concentration as a function of volume of liquid added was biphasic: initially flat and then rising linearly. This is qualitatively similar to data reported previously for halothane. The authors hypothesize that drying soda lime produces a molecular sieve-like structure, as adsorption is greatest for molecules with small carbon chain lengths and kinetic diameters, or with structural characteristics such as cis/trans isomerism, which effectively reduce molecular size.

Effect of Sleep State on the QT Interval in Normal Infants

Summary: Twenty QT intervals selected at random from the middle periods of rapid eye movement (REM) and quiet sleep were measured in 12 normal infants studied at 2 weeks and 1, 2, 3, and 4 months of life. A digitizing system, consisting of a precision rotational potentiometer mounted on a pair of calipers and an A/D converter, was used for measurements. An accuracy of ±2 msec was achieved by high resolution of the digitized signal and calibration of each QT measurement with an accurately generated time code. Sleep staging was done visually using an electroencephalogram (EEG), an electrooculogram (EOG), a submental electromyogram (EMG), and behavioral criteria. Our results show that the QT index (QTc = QT/□RR was significantly greater during quiet sleep (mean = 0.439) than during REM sleep (mean = 0.433) (P < 0.01) and that this difference existed at all ages studied.Speculation: Sleep states are shown to have detectable effects on the duration of ventricular repolarization as measured by the QT interval. We speculate that this sleep state-related difference in the QT interval may be caused by an increased sympathetic activity in REM sleep.

Occult positive end-expiratory pressure with different types of mechanical ventilators

Abstract During mechanical ventilation under conditions which provide insufficient time for exhalation, expiration is incomplete and lung volume is elevated above the level expected. In turn, this results in an increase in alveolar end-expiratory pressure above applied end-expiratory pressure. We expect these increases to depend on the ratio of expiratory time to the time constant (resistance times compliance) of the respiratory system. However, the application of this simple concept varies according to the type of ventilator used. Under extreme conditions, volume-cycled ventilators may produce an increase in end-expiratory lung volume greater than the delivered tidal volume. Time-cycled, pressure-limited respirators offer some protection against such large increases, but at the cost of a reduction in tidal volume from that expected for the chosen pressures.

988 HEART RATE AND HEART RATE VARIABILITY IN NORMAL AND ABORTED SIDS INFANTS DURING SLEEP

Heart rate (HR) and HR variability were studied in 15 normal infants and 6 infants with aborted Sudden Infant Death Syndrome (SIDS) during sleep at monthly intervals through 4 months of age. The RR interval (inverse of heart rate) was measured to an accuracy of 0.2 msec. Sleep was staged using EEG, EOG, EMG and behavioral criteria.The median HR was 4 to 10% greater in the aborted SIDS infants at each age in both sleep states and this was significant at 2,3 and 4 months in quiet and at 3 months in REM sleep (p < 0.05, Wilcoxon Rank Sum test). The beat to beat variability of the HR (Δ RR) in the aborted SIDS infants was 6 to 40% smaller than in the normal infants in both REM and quiet sleep at each age studied. The interquartile range of the HR, a measure of overall variability in HR, was the same in the aborted SIDS and normal infants. In both groups, the HR and its interquartile range were greater in REM sleep.These studies indicate that the group of infants with aborted SIDS may be differentiated from the normal infants by their increased heart rate and decreased beat to beat variability, and that these findings may reflect abnormal autonomic regulation of the heart rate.