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Dietary sodium restriction is used in the Netherlands in the prophylaxis of preeclampsia. To study the effects of long-term sodium restriction on the intake of other nutrients and the outcome of pregnancy, 68 healthy nulliparous pregnant women were randomly assigned to either a low-sodium diet (20 mmol/24 h) or an unrestricted diet. The diet was consumed between week 14 of gestation and delivery. The dietary intakes of energy, fat, protein, carbohydrate, sodium, potassium, and calcium were estimated with the dietary-history technique. A low-sodium diet reduced the intake of protein (by approximately 15 g/24 h), fat (by 20 g/24 h), and calcium (by 350 mg/24 h) and tended to decrease the energy intake (by approximately 0.7 MJ/24 h). The intakes of carbohydrate and potassium did not differ between the groups. The maternal weight gain was less in the low-sodium group (6.0 +/- 3.7 compared with 11.7 +/- 4.7 kg). Mean birth weight was not significantly different (3.2 +/- 0.5 compared with 3.4 +/- 0.5 kg).

Myocytes are electrically coupled by gap junctions, which are composed of low-resistance intercellular channels. The major cardiac gap junction protein is connexin43 (Cx43). The distribution of Cx43 has been studied by immunofluorescence to visualize the electrical coupling between atrial tissue and sinoatrial node. From modeling studies, this coupling was inferred to be gradual in order to shield the sinoatrial node from the atrial hyperpolarizing influence. The actual Cx43 labeling pattern did not show the expected gradient but instead a rather black and white staining in a striking pattern of strands of cells. We used an immunohistochemical marker (anti-alpha-smooth muscle actin [alpha SMA]) that specifically cross-reacts with guinea pig sinoatrial node cells together with Cx43 antibody to stain previously electrophysiologically mapped sinoatrial nodes. We found that in the guinea pig sinoatrial node the impulse originates in an alpha SMA-positive, virtually Cx43-negative, region (primary pacemaker region). The impulse then travels obliquely upward to the crista terminalis through a region where layers of alpha SMA-positive cells alternate with layers of Cx43-positive SMA-negative cells. The layers of Cx43-positive cells appear to become broader and thicker in the direction of the crista terminalis, whereas the layers of alpha SMA-positive cells become thinner and narrower. Lateral contacts between Cx43- and alpha SMA-positive cells were very sparse and only detected where the Cx43-positive strands ended (the region where alpha SMA-positive cells fill the whole space between endocardium and epicardium, ie, the putative primary pacemaker region). From these results, we conclude that the primary pacemaker is shielded from the hyperpolarizing influence of the atrium by a gradient in coupling brought about by tissue geometric factors rather than by a gradient of gap junction density.

Objective: We studied the relationship between preductal arterial oxygen saturation and metabolic acidosis in 18 chronically instrumented fetal lambs (gestational age 119 to 133 days) in two experimental designs. In the first group the onset of metabolic acidosis was determined. In the second group the progression of metabolic acidosis was studied as was the cardiovascular and hormonal changes resulting from hypoxemia., Study Design: In nine fetal lambs maternal fraction of inspired oxygen was lowered stepwise by increasing flows of nitrogen delivered into the trachea through a small indwelling catheter (group 1), and in nine fetal lambs maternal blood flow was reduced stepwise by means of a vascular occluder (group 2)., Results: Baseline arterial oxygen saturation values ranged from 26% to 67% with normal pH and extracellular fluid base excess values in both groups 1 and 2. In both groups pH and extracellular fluid base excess started to decrease below 30% arterial oxygen saturation, with a progressive decrease below 20% arterial oxygen saturation to an end value for pH of 7.14. In some fetal lambs pH and extracellular fluid base excess decreased initially at 20% to 30% arterial oxygen saturation and then stabilized at the lower level. Fetal heart rate in group 1 increased during hypoxemia from 155 to 179 beats/min. In group 2 baseline fetal heart rate was 153 beats/min and fell with every step change in arterial oxygen saturation but subsequently increased to 172 beats/min by the end of the period of hypoxemia. Baseline values for epinephrine, norepinephrine, dopamine, cortisol, and mean arterial pressure were not related to baseline arterial oxygen saturation levels, and each of these variables was increased at the end of hypoxemia in group 2., Conclusion: Preductal arterial oxygen saturation can reach values between 20% and 30% before anaerobic metabolism starts. During the progressive acidosis blood pressure was increased, which can be attributed to a strong rise in catecholamines.

Objective: The objective of our study was to describe the results from human experiments during normoxia that demonstrate the effect of pulsating arteries on the measured arterial oxygen saturation (SpO2) using a reflectance pulse oximeter sensor., Methods: In 6 healthy adults and 7 healthy neonates, a Nellcor reflection sensor (FS-10 oxisensor, Nellcor, Inc., Pleasanton, CA) was placed in three different positions: (1) on the forehead, (2) on the temporal area, with the photodiode placed over the superficial temporal artery, and (3) on the temporal area, with the light-emitting diodes (LEDs) placed over the superficial temporal artery., Results: Placement of the sensor in position 2 resulted in a significantly lower SpO2 reading, compared to sensor position 1: 5.8% (p < 0.01) lower for adults and 7.5% (p < 0.01) lower for neonates. Placement of the sensor in position 3 resulted in significantly larger plethysmographic signals, compared to sensor position 1; but, the Spo2 readings were alike., Conclusions: Pulsating arteries can affect the reliability of reflection pulse oximetry. Depending on the position of the sensor, a falsely low Spo2 value can be observed.

Background: Most laboratory parameters change during pregnancy. A serial study of a large number of routine haematological and biochemical blood parameters and biochemical urine parameters was conducted in a group of 66 healthy nulliparous pregnant women, who had an uncomplicated pregnancy., Methods: Blood samples and 24-h urine samples were obtained at four weeks intervals during pregnancy and at 1 (1P) and 6 (6P) weeks after delivery., Results: During pregnancy, haemoglobin concentration, haematocrit and erythrocyte count were lower, mean cell volume was not different, and mean cell haemoglobin and mean cell haemoglobin concentration were enhanced. The platelet count during pregnancy was not different from the level at 6P but increased 60% at 1P. Serum ferritin decreased 50% whereas plasma fibrinogen increased 100%. Serum creatinine (-28%), uric acid (-35%) and urea (-40%) concentrations were reduced during pregnancy. The serum concentrations of sodium (-4 mmol/l) and potassium (-0.2 mmol/l) were lower, but serum chloride was unaltered. Serum protein and albumen concentrations declined by 7.8 and 9.4 g/l respectively. The serum concentrations of bilirubin, ALAT, ASAT and gamma-GT remained unaltered. Serum LDH was 30% above normal non-pregnant values at 1P. The heat-stable alkaline phosphatase level increased in the third trimester. Heat-stable and heat-labile fractions were both elevated at 1P. The serum osmolality was 9 mosmol/kg lower and urine volume was about 25% higher during pregnancy. The creatinine excretion was unaltered but creatinine clearance increased by 25%., Conclusions: The concentrations of most components change during pregnancy. The interpretation of results of laboratory tests in pregnant women should be made with caution.

The development of fetal behaviour and of fetal behavioural states (FBS) has been well defined in preterm and term fetuses. However, FBS have not yet been studied after term, although this is a potentially very dangerous period and clinical management is controversial. We investigated fetal behaviour in normal pregnancies after 41 weeks of gestation (287 days, menstrual age, GA) as compared to control term fetuses. Furthermore, we wanted to see if the findings might have consequences for clinical management. Twelve healthy women with GA between 289 and 298 days participated. All pregnancies were reliably dated and at the time of the study, there was a normal amount of fluid. Twelve healthy women with GA 273-287 days served as controls. All subjects underwent a behavioural study using cardiotocography to record the heart rate (CTG), and two ultrasound scanners to observe body and eye movements, as described previously. All fetuses in both groups clearly exhibited FBS 1F-4F which fitted the definitions of Nijhuis et al. The median percentage of FBS 3F and 4F ('awake states') increased significantly from 6% in the term group to 21.5% in the fetuses after 41 weeks (P = 0.014). FBS 1F ('quiet sleep') and 2F ('active sleep') decreased from 92 to 78% (P = 0.014), mainly at the expense of FBS 2F which decreased from 78 to 58% (P = 0.002). This indicates increasing wakefulness in utero. The fetal heart rate patterns (FHRP) associated with FBS 3F and 4F were impressive. For example, in FBS 4F, the FHRP showed large amplitude, prolonged accelerations which fused into a sustained tachycardia with only short periods of return to the baseline, resembling tachycardia with decelerations. We conclude that in normal pregnancies after 41 weeks, the development of the fetal central nervous system continues, resulting in an increasing percentage of 'fetal wakefulness'. The CTG-patterns that result from these behaviours can easily mimic fetal distress and one should be aware of this phenomenon. Whether behavioural studies can be used to distinguish 'normal' from 'abnormal' fetuses after term awaits further study.

Background: In cases of fetal congenital heart block, the fetal heart rate (FHR) pattern is uninterpretable, often leading to an operative delivery. Reflectance pulse oximetry, a new technique that continuously measures the fetal arterial oxygen saturation (SaO2) during labor, is potentially useful in intrapartum monitoring of fetuses with this condition., Cases: Two fetuses with congenital heart block were monitored with reflectance pulse oximetry and fetal scalp blood sampling. The first patient delivered spontaneously. Adequate signal quality was achieved during 73% of the study time. Mean +/- standard deviation (SD) SaO2 was 53 +/- 14%. Fetal outcome was good. The second patient was delivered by cesarean because of arrest of labor. Oxygen saturation values were obtained during 89% of the study time. The mean SaO2 was 42 +/- 13%. There was a period of 8 minutes with SaO2 values below 20%. Capillary blood pH dropped from 7.33 to 7.25; SaO2 values then returned to levels above 30% and the capillary blood pH normalized. The neonate was born in good condition., Conclusion: In fetal congenital heart block, adequate surveillance with FHR monitoring during labor is not possible; therefore, continuous information on fetal oxygenation may be valuable in assessing the fetal condition and may prevent unnecessary obstetric interventions.

Objectives: Our purpose was to study fetal arterial oxygen saturation trends by continuous pulse oximetry during labor in subjects with normal and abnormal delivery outcomes., Study Design: Continuous fetal arterial oxygen saturation was measured during labor with a noninvasive reflectance pulse oximeter designed for fetal application. Averaged arterial oxygen saturation values were compared between stage 1 and stage 2 of labor, with stage 1 further subdivided into early (< or = 4 cm), middle (5 to 7 cm), and late (8 to 10 cm) phases. Delivery outcome was considered to be abnormal for any of the following conditions: gestational age < 37 weeks, maternal oxygen administration, delivery by cesarean section, 5-minute Apgar score < 7, umbilical artery pH < 7.10, birth weight < 2500 gm, or newborn intensive care unit admission., Results: A total of 291 subjects were studied: 142 in Provo, 90 in Nijmegen and 59 in San Francisco. Subjects with delivery complications (n = 125) were evaluated separately from those with normal delivery outcomes (n = 160). Fetal arterial oxygen saturation was 58% +/- 10% (mean +/- SD) during the cumulative period of study for the normal-outcome group. A significant decrease (paired t test, p < 0.001) in fetal arterial oxygen saturation occurred from stage 1 (59% +/- 10%) to stage 2 (53% +/- 10%) labor. When stage 1 was subdivided into early (< or = 4 cm), middle (5 to 7 cm), and late (8 to 10 cm) phases, a gradual decreasing trend in fetal arterial oxygen saturation was observed: 62% +/- 9%, 60% +/- 11%, and 58% +/- 10%., Conclusions: With the use of reflectance pulse oximetry, a statistically significant decrease in fetal arterial oxygen saturation was observed during labor in women with normal and abnormal delivery outcomes.

Experimental pulse oximetry devices, similar to the existing systems used in adult and neonatal monitoring, can be used on the fetus to provide safe, and rapid information about oxygenation. They have been calibrated using fetal lambs and validated in human cross-sectional studies. Experiments have shown that fetal oxygen saturation decreases during normal labour, and drops after a uterine contraction especially with oxytocin-induced tachysystole. When the mother is given oxygen the fetal oxygen saturation increases. Readings are effected by caput and movement, and trends seem to be more meaningful than absolute values. Pulse oximetry can predict fetal outcome and a normal oxygen saturation result is specific for a good outcome perhaps even if the CTG is abnormal. However the technique is still experimental and there is insufficient data to support its use as a replacement for fetal blood sampling or a discriminator for an abnormal fetal heart trace.

In the fetus, the arterial oxygen saturation (SaO2) in the ascending aorta is higher than in the descending aorta. We questioned whether this difference over the ductus arteriosus (delta SaO2) would change during hypoxaemia. Therefore, six chronically instrumented fetal lambs (119-126 days of gestation) were studied, by changing the inspired oxygen (FIO2) via a tracheal tube to the ewe. The SaO2 was measured intermittently every 15 min with blood samples obtained from the ascending and descending aorta, and continuously with 2 pulse oximeters at both sides of the ductus arteriosus. delta SaO2 was at a level of 3.4-5.3% and had a tendency to decrease at preductal SaO2 levels of 10-20% and at pH levels below 7.25. The precision of the pulse oximeters, expressed as standard deviation of the differences between sample SaO2 and pulse oximeter SaO2, was around 5.0% for the individual calibration curves. This precision was not enough to show details of the course of delta SaO2 between the blood samples. Our results show that there is no change in delta SaO2 across the ductus arteriosus.

Single pacemaker heart cells discharge irregularly. Data on fluctuations in interbeat interval of single pacemaker cells isolated from the rabbit sinoatrial node are presented. The coefficient of variation of the interbeat interval is quite small, approximately 2%, even though the coefficient of variation of diastolic depolarization rate is approximately 15%. It has been hypothesized that random fluctuations in interbeat interval arise from the stochastic behavior of the membrane ionic channels. To test this hypothesis, we constructed a single channel model of a single pacemaker cell isolated from the rabbit sinoatrial node, i.e., a model into which the stochastic open-close kinetics of the individual membrane ionic channels are incorporated. Single channel conductances as well as single channel open and closed lifetimes are based on experimental data from whole cell and single channel experiments that have been published in the past decade. Fluctuations in action potential parameters of the model cell are compared with those observed experimentally. It is concluded that fluctuations in interbeat interval of single sinoatrial node pacemaker cells indeed are due to the stochastic open-close kinetics of the membrane ionic channels.

In mammalian myocardium, myocytes are electrically coupled by gap junctions, which are collections of membrane channels spanning the intercellular gap. Each channel is composed of twelve protein molecules--six in each membrane--enclosing a pore of 2 nm diameter. In addition to the main cardiac gap junction protein connexin 43 (cx43), two other constituents, connexin 40 (cx40) and connexin 45 (cx45), recently have been identified. In this study, the ultrastructural distribution of cx40 has been traced in several mammalian cardiac tissues, using a specific antibody and immunogold labeling. In rabbit, cx40 was found in gap junctions between myocytes of the right atrium as well as in the false tendons of the left ventricle. Labeling within the free ventricular wall could be obtained only with higher primary antibody concentrations. In rat atrial and ventricular working myocardium a similar distribution of label was observed. Double labeling of cx40 and cx43 in rat atrium, with 5 nm and 15 nm gold particles respectively, demonstrates limited patches of cx40 in gap junctions otherwise homogeneously labeled for cx43. Since cx40 has a much higher single channel conductance than cx43, topographical differences in their relative distribution might contribute to regional differences in conduction velocity of the cardiac impulse.

The electrical properties of gap junctions in cell pairs are usually studied by means of the dual voltage clamp method. The voltage across the junctional channels, however, cannot be controlled adequately due to an artificial resistance and a natural resistance, both connected in series with the gap junction. The access resistances to the cell interior of the recording pipettes make up the artificial resistance. The natural resistance consists of the cytoplasmic access resistances to the tightly packed gap junction channels in both cells. A mathematical model was constructed to calculate the actual voltage across each gap junction channel. The stochastic open-close kinetics of the individual channels were incorporated into this model. It is concluded that even in the ideal case of complete compensation of pipette series resistance, the number of channels comprised in the gap junction may be largely underestimated. Furthermore, normalized steady-state junctional conductance may be largely overestimated, so that transjunctional voltage dependence is easily masked. The model is used to discuss conclusions drawn from dual voltage clamp experiments and offers alternative explanations for various experimental observations.

In an attempt to understand better the directional differences in conduction velocity in the rabbit sinoatrial node, a possible conductive role of the abundant connective tissue surrounding the myocytes has been investigated. In particular, starting from the finding of communicating junctions between heart muscle cells and fibroblasts in tissue culture, heterologous gap junctions were searched for in thin sections of the rabbit sinoatrial node. Within and at the edge of nodal cell clusters, fibroblasts often show thin sheet-like extensions parallel to the surface of myocytes. In contrast to the intimately contacting myocytes, fibroblast extensions are kept separated from the myocytes by the basement membrane of the latter. Besides some rare undefined membrane appositions a single tiny gap junction-like structure was found between a fibroblast and a myocyte in a tissue area in which the calculated number of gap junctions between myocytes amounts from 1.10(4) to 3.10(4). Yet, fibroblasts are linked together regularly by small gap junctions containing a wider gap than the junctions between the myocytes (1.4 +/- 0.4 nm vs. 1.0 +/- 0.4 nm, resp., P less than 0.05). As an alternative to direct electrical coupling, the possibility of interaction between fibroblasts and nodal cells by capacitive coupling has been considered. Model calculations based on the reconstruction of some fibroblast extensions parallel to nodal cells show that the current which can be transmitted from discharging nodal cells to fibroblasts is negligible. It is concluded that fibroblasts do not participate in the impulse conduction within the sinoatrial node. The origin of the directional differences in conduction velocity in the sinoatrial node must be found in the spatial arrangement of the myocytes and the distribution of the gap junctions between these cells only.

Intra-uterine pressure (IUP), intracranial pressure (ICP) and fetal heart rate (FHR) were simultaneously recorded during labor in a severely hydrocephalic fetus. After cephalocentesis, 600 ml of liquor cerebrospinalis was drained. ICP exceeded IUP, but the increase in ICP was less than the increase in IUP during most of the contractions. The FHR showed marked decelerations during uterine contractions and changed gradually into a persistent bradycardia. The pathophysiology of fetal heart rate patterns during labor is discussed and the literature has been reviewed.

In a European collaboration, a joint project to conduct an experimental and clinical investigation of recently developed sensors from three centres (Amsterdam, Cambridge and Edinburgh) has been carried out. The Amsterdam sensor was based on an inductive principle whereas the Cambridge and Edinburgh transducers used a piezo-electric material (PVDF) as transducing element. Nine patients with varying gestational age (29-38 weeks) were measured in a clinical investigation. Recordings of fetal heart sounds (FHS) and fetal breathing movements (FBM) were made using three sensors; one from each centre. These recordings were digitized directly into a computer using a purpose-built data acquisition system. For each patient 3 min of FBM data, and 1 min of FHS data were recorded by each sensor. The FBM recordings were carried out simultaneously with ultrasound, so as to enable a correlation to be made between both recordings. The FHS recordings were carried out simultaneously with the maternal heart pulse, to discount any maternal heart influences on the resulting signals. Of the nine patients analysed, FHS were recorded in seven patients. On the other hand, it appeared difficult to identify fetal breathing movements in the FBM recordings due to the dominance of the maternal breathing component. The analysis of the FBM signals and its correlation with ultrasound could not be carried out due to the relatively poor quality of the signals detected by the sensors, given the present techniques of analysis. The evaluation of the FHS recordings showed that although there is relatively little difference between the sensors, the inductive sensor performed best.

In the past decade, three mathematical models describing the pacemaker activity of the rabbit sinoatrial node have been developed: the Bristow-Clark model, the Irisawa-Noma model, and the Noble-Noble model. In a comparative study it is demonstrated that these models, as well as subsequent modifications, all have several drawbacks. A more accurate model, describing the pacemaker activity of a single pacemaker cell isolated from the rabbit sinoatrial node, was constructed. Model equations, including equations for the T-type calcium current, are based on experimental data from voltage clamp experiments on single cells that were published during the last few years. In contrast to the other models, only a small amount of background current contributes to the overall electrical charge flow. The action potential parameters of the model cell, its responses to voltage clamp steps and its current-voltage relationships have been computed. The model is used to discuss the relative contribution of membrane current components to the slow diastolic depolarization phase of the action potential.

Objective: To study the possible pathophysiological implications of long continued dietary sodium restriction in pregnancy., Design: Longitudinal prospective randomized study of the effects of a low sodium diet compared with unrestricted sodium intake in pregnancy., Setting: Academic Department of Obstetrics and Gynaecology at Sint Radboud Hospital, Nijmegen, The Netherlands., Subjects: 42 healthy nulliparous women., Intervention: A low sodium diet (20 mmol sodium daily) started in the 14th week of pregnancy and stopped after delivery., Main Outcome Measures: Maternal weight gain, food intake, blood pressure, cardiac output, systemic vascular resistance, haematocrit and birthweight., Results: Total maternal weight gain and dietary energy intake during pregnancy and weight at 1 and 6 weeks postpartum were significantly lower in the low sodium group. Blood pressure during pregnancy did not show major differences. Stroke volume and cardiac output during pregnancy were significantly lower in the low sodium group whereas systemic vascular resistance was significantly higher. Haematocrit values in the low sodium group tended to be lower during pregnancy, but were significantly lower at 1 and 6 weeks postpartum than in the unrestricted group. Placental and birthweights were not significantly different between the two groups., Conclusions: Chronic dietary sodium restriction during pregnancy is characterized by a diminished body fat accumulation and a reduction in circulating volume, due to a decrease in both plasma and red cell volume, in combination with a high systemic vascular resistance without major effects on blood pressure and birthweight.

This article reviews the major milestones in obstetric research in the past 90 years, which have lead to the wide-spread use of salt restriction during pregnancy. Possibly the most ardent advocate of the view that salt plays a crucial role in eclampsia was De Snoo (1877-1949), a Dutch obstetrician. However, despite many enthusiastic clinical reports, no convincing evidence has ever been produced that salt restriction helps in the prevention of hypertension during pregnancy.

This paper describes the experimental studies and results of a collaborative investigation between three European institutes: Amsterdam, Cambridge and Edinburgh. The object of this investigation and the collaborative exchanges was to evaluate and compare different sensors for recording fetal sounds and movements from each centre. This would be carried out in a series of experimental and clinical tests involving researchers from each of the European institutes, and using three sensors: one from each centre. Experimental measurements have been performed regarding the conversion gain, frequency response, equivalent input noise and dynamic range of the transducers. The measurements were carried out using a vibration-free table testing rig to evaluate these characteristics of each of the sensors. The equivalent input noise ranged from 50 nm to 1600 nm for the transducers studied.

Chloroquine is frequently used during pregnancy in malaria-endemic countries, but no data are available about fetal exposure to the drug. Prophylactic use during labour to obtain effective concentrations in the newborn is also documented. In the present study, the placental transfer of chloroquine was investigated in the pregnant, near-term sheep model. Chronic catheterization allowed blood sampling of maternal and fetal blood. Following a single intramuscular injection or intravenous infusion to the ewe, chloroquine was slowly distributed to the fetus. Peak concentrations in the fetus reached up to +/- 280 ng/ml within 2-4 h after administration while maximal concentrations in the mother reached up to 2,850 ng/ml. The terminal half-life of chloroquine in pregnant sheep was very long, amounting to 65.1 +/- 34.9 h (range 27.4-119 h). Tissue binding was high, as reflected by the extensive volume of distribution (V(area): 19.0 +/- 11.0 l/kg). Total clearance was equal to 3.42 +/- 0.60 ml/min/kg. The transfer rate of chloroquine from the mother to the fetus was low in all animals. So, the placenta is quite an effective barrier for the drug.

The validity of the diagnosis fetal distress based on electronic fetal monitoring (EFM) is low. It can be argued that the prediction of fetal distress may be influenced by the obstetric intervention, and a number of false-positive (FP) decisions are in fact cases of successful prevention of acidosis. The false-negative decisions (FN) may include cases in which an operative delivery was not performed, although the impaired fetal condition was correctly recognized. To estimated the magnitude of these effects, deliveries after 28 weeks of gestation, in which EFM was applied, were studied. The medical staff involved in these deliveries was asked to estimate the umbilical artery pH immediately before birth. After birth the pH was measured. Cases were classified as operative delivery for fetal distress or other. Fetal distress was supposes to be confirmed if the umbilical artery pH was less than or equal to 7.14. Pre-birth estimates of the pH were obtained in 393 cases. Of the 20 FP cases, 70% were real FP after considering the prebirth estimate; of the 35 FN cases, 89% were real FN. After correction for mistaken false results the sensitivity increased from 20.5% to 29.5% and the predictive value from 31.0% to 51.7%. Although validity and predictive values improve after correcting for the mistaken false results, their values are still unsatisfactorily low.

The time course of gap junction formation and growth, following contraction synchronization of cardiac myocytes in culture, has been studied in a combined (electro) physiological and ultrastructural study. In cultures of collagenase-dissociated neonatal rat cardiocytes, pairs of spontaneously beating myocytes synchronized their contractions within one beat interval within 2-20 min after they apparently had grown into contact. 45 sec after the first synchronized beat an appreciable junctional region containing several small gap junctions was already present. In the following 30 min, neither the area of individual gap junctions nor their total area increased. 75 min after synchronization both the area of individual gap junctions and their total area had increased by a factor of 10-15 with respect to what was found in the first half hour. In the period between 75 and 300 min again no further increase in gap junctional area was found. In double voltage-clamp experiments, gap junctions between well-coupled cells behaved like ohmic conductors. In poorly coupled cells, in which the number of functional gap-junctional channels was greatly reduced, the remaining channels showed voltage-dependent gating. Their single-channel conductance was 40-50 pS. The electrophysiologically measured junctional conductance agreed well with the conductance calculated from the morphometrically determined gap-junctional area. It is concluded that a rapid initial gap junction formation occurs during the 2-20 min period prior to synchronization by assembly of functional channels from existing channel precursors already present in the cell membranes. It then takes at least another 30 min before the gap-junctional area increases possibly by de novo synthesis or by recruitment from intracellular stores or from nonjunctional membranes, a process completed in the next 45 min.

Based upon a previously described procedure for automated baseline determination in antepartum fetal heart rate recordings, a programme has been developed for recognition of accelerations and decelerations. Detection of these deviations from the baseline depends on criteria for amplitude and duration, with special account for signal loss. The described automated analysis provides an objective tool for description of antepartum fetal heart rate patterns. A first evaluation with respect to its capacity to discriminate between different fetal heart rate patterns in relation to fetal rest-activity patterns shows promising results.

A consequent and reproducible determination of baseline is an essential prerequisite for objective interpretation of fetal heart rate. A fully automated off-line method of baseline determination has been developed and tested on 50 normal antepartum fetal heart rate recordings of two hours duration. The method is constructed around two functional units, a digital filter and a trim function, which interact in an iterative process. The results were evaluated in comparison with automated baseline determination according to Dawes and coworkers. A panel of 3 experts agreed that in 14 of the 50 recordings (28%), the new developed procedure resulted in a substantially better baseline fit. In the remaining 34 recordings (72%), baseline fit from both methods was judged as equivalent. The described procedure of baseline determination provides a solid base for automated detection of accelerations and decelerations in fetal heart rate recordings. It enables the study of the relation between the fetal heart rate pattern and fetal movements. Finally, it provides an objective tool for analysis of variables within the fetal heart rate with the highest predictive value with respect to fetal outcome.

Electrotonic current spread in the SA node of the rabbit was measured by means of hyperpolarizing current pulses (1 to 10 microA, 60 ms), which were injected intracellularly through a K(+)-perfused suction electrode. The pulses were applied at the beginning, middle or end of the diastolic depolarization phase. The resulting membrane potential change of nodal fibers was measured with microelectrodes. Space constants were calculated by fitting single exponential curves to the data. The input resistance (Rin) of fibers at different sites in the SA node was measured by means of a double barrel microelectrode (current pulses 5.5 to 11 nA, 60 ms) to detect a change in the internal resistance during the diastolic depolarization phase. During diastole the average electrotonic potential increased by 30% (P less than 0.001), the increase of the space constant ranged from 9 to 183% (P less than 0.05). Rin however, did not change during diastole. It is concluded that the electrotonic spread increased phase dependently, due to an increase of membrane resistance; the internal resistance was not phase dependent.

We describe the phase-resetting effect of injecting an isolated current pulse in an ionic model of a single cell of the sinoatrial node. Delivery of a depolarizing pulse early (late) in the cycle results in a prolongation (abbreviation) of the cycle length. With a hyperpolarizing pulse, the effect is reversed. We determine the topological type or degree of phase resetting in two ways: 1) by analyzing interbeat intervals extracted from the voltage waveform, and 2) by analyzing the waveform, not only of the voltage, but of all the activation and inactivation variables. The two methods give similar results. At low (high) pulse amplitudes, there is type 1 (0) phase resetting. When type 1 phase resetting occurs, the new phase is a monotonically increasing function of the old phase at sufficiently low stimulus amplitudes, whereas at higher stimulus amplitudes it is not. Leading roles in generating phase resetting are attributed to the slow inward current and to the leakage current. Comparison is made with experimental phase-resetting findings in the sinoatrial node and other cardiac oscillators. Implications for unidirectional and bidirectional synchronization are also sketched out.

The effects of dietary sodium restriction and posture on plasma concentrations of atrial natriuretic peptide (ANP), aldosterone and free aldosterone were investigated in ten women between weeks 29 and 33 of normal pregnancy. Hormone levels were studied during unrestricted sodium intake and on day 6 of a low sodium diet. On both occasions venous blood was obtained in the sitting as well as in the left lateral tilt position. Plasma concentrations of ANP during the unrestricted sodium intake were not raised compared with control values in healthy non-pregnant females. Recovery experiments showed no differences in the degradation of ANP in blood from pregnant and non-pregnant women. Plasma concentrations of ANP significantly decreased (by 32%) in response to the low sodium regime in both positions. Concentrations of aldosterone and free aldosterone (in women in the sitting position) increased twofold after sodium restriction. Mean values of ANP were higher in women in the left lateral tilt position that in those in the sitting position, but the difference was not significant. Concentrations of aldosterone and free aldosterone were significantly lower (by around 30%) in women in the left lateral tilt position compared with those in the sitting posture.

Synthesis and secretion of atrial natriuretic peptide (ANP) is not confined to the heart, but also present in other tissues. ANP is known to affect steroidogenesis in the ovary. To assess the possibilities that (a) the human ovary is a source of ANP secretion as well, and (b) ovarian ANP stimulates progesterone secretion, we investigated ANP as well as progesterone concentrations in preovulatory ovarian follicular fluid form women in an in vitro fertilization program. In all women detectable ANP immunoreactivity was found in ovarian follicular fluid (range 3.3-60.1 pg/ml). Follicular fluid concentrations were low in all but 1 women who demonstrated a higher ANP level in follicular fluid than in plasma. Follicular ANP and progesterone concentrations were not significantly correlated. These preliminary results suggest that the ovary could well be a site of ANP secretion. If and how ovarian ANP activity affects progesterone secretion remains as yet unknown.

In voltage clamped neonatal rat heart cells a transient current is observed during depolarizing potential steps, which was identified as slow inward current (Isi) by its range of activation, by its reversal potential of approximately +50 mV and by its sensitivity to D600 or low external Ca2+. This Isi activates too fast to be detected by the present methods, which implies that activation is completed within milliseconds. The time constant of inactivation was weakly potential dependent and less than 30 ms between -40 mV and +20 mV. The f infinity curve of Isi had a sigmoidal shape with 90% and 10% values near -50 mV and -10 mV respectively, half maximum was at -25 mV. From double pulse experiments an estimate was obtained of the potential dependence and amplitude of steady state Isi. A maximum was expected around -30 mV. Steady state Isi appears to be present indeed in steady state current voltage relations, as the relative minimum at -30 mV in such relations is abolished by 5 X 10(-7) g/ml D600. Currents tails during hyperpolarizing steps from prepulse potentials near 0 mV are potential dependent in a way expected when Isi contributes to these current tails by a decrease in inactivation. Moreover, the current tails are diminished by D600 or Co2+. Consequences of steady state Isi are discussed.

Maternal diazepam medication during labor reduces beat-to-beat variability of the fetal heart rate. In this study, the prolongation of the effect was examined in the newborn. The mother received diazepam: (A) during labor as a tranquilizer, (B) daily in low doses at the end of pregnancy, or (C) in high doses i.v. for (pre-)eclampsia. A control group had no analgesic or sedative during pregnancy or labor. The electrocardiogram (ECG) was recorded daily from each newborn during the first 6 days after birth. After preprocessing of the ECG, the median R-R interval, the long-term irregularity index (LTI index) and the interval difference index (ID index) were calculated. A cubic spline interpolation method was applied to compare the various groups with respect to these heart rate parameters. The median R-R interval showed no particular differences in trend for all groups. The LTI index was decreased in the first days after birth in the chronic diazepam (B), and in the diazepam infusion groups (C), but statistical significance was not reached. The ID index was significantly decreased in the first 1-2 days in the newborns of the acute and chronic diazepam group. In the diazepam infusion group, an even longer lasting effect was observed. Maternal diazepam medication affects the beat-to-beat variability in the newborn. The duration of the effect is dependent on dosage and route of administration.

The rhythmicity of human fetal breathing movements was studied during two different behavioural states (1F and 2F, respectively), using real-time B-scan-directed M-mode ultrasound recordings. The mean breath-to-breath interval durations and the standard deviations (SD), and the standard deviations of the interval differences (SDDSI) were calculated. The mean breath-to-breath interval duration was not significantly shorter during 1F than during 2F. SD and SDDSI, however, showed significantly lower values during 1F, demonstrating that the fetal breathing rhythm is more regular during state 1F than during state 2F epochs. Regular fetal breathing is thus a concomitant of state 1F.

Three different bradycardic agents, alinidine, AQ-A39 and UL-FS49 increase the intrinsic cycle length of the isolated SA node preparation of the rabbit. This increase is mainly caused by a decrease in rate of diastolic depolarization. One of these agents, alinidine, was used to study the underlying ionic mechanism of the decrease in the diastolic depolarization rate in isolated cells and small cell clusters of the rabbit SA node. In these preparations alinidine slowed down the rate of spontaneous activity at higher concentrations (80 microM). At lower concentrations (10 microM) the decrease in rate of spontaneous activity was variable, but injection of a hyperpolarizing current slowed the spontaneous rate more in the presence of alinidine, indicating an increase in membrane resistance. In voltage clamp experiments we found that the main effect of alinidine was a block of the hyperpolarization activated current if. The block was potential dependent and was maximal in the potential range in which diastolic depolarization occurs. These results are discussed in relation to previous findings of others.

Eight chronically instrumented fetal sheep were asphyxiated for 1 h by partial occlusion of the uterine blood supply. Fetal movements, as reflected by phasic activity in the nuchal electromyogram, decreased during the period of asphyxia. Tonic activity also decreased. The proportion of time spent in high-voltage electrocortical activity increased. Following release of the occlusion movements returned rapidly to the level present during the control period. The distribution of electrocortical activity patterns during the recovery period was similar to that during the control period.

Plasma concentrations of atrial natriuretic peptide (ANP) were determined ante- and post-partum in 7 healthy primiparous women. ANP was measured at weekly intervals from the 35th week of pregnancy onwards and throughout the puerperium up to the sixth week post-partum. In all seven patients the mean of the ANP values during the first four days post-partum was higher than in late pregnancy. The mean ANP level from the 6th day up to the 42nd day showed a marked decrease compared with the first four days after birth, which, however, did not differ significantly from the mean plasma concentration in late pregnancy. In conclusion, ANP is markedly elevated during the first few days post-partum compared with plasma levels in the normal late pregnancy and the subsequent puerperium.

Intraamniotic pressure was studied in the 30th week of amenorrhea in relationship with fetal intracranial pressure with open-tip catheters. The fetus had a severe hydrocephalus (echoscopy 16 cm) due to a teratologic malformation of the cerebrum. Clinically nonoperative treatment was indicated. Intracranial pressure (X) was invariably higher than intraamniotic pressure (Y) between contractions: Y = 2.04 + 0.54 X, and during contractions: Y = 5.30 + 0.55 X. There was no definite relationship between intrauterine and intracranial pressure, and the fetal tachogram. A definite relationship was established with the supine position of the patient and decelerations in the fetal tachogram. It is suggested that when fetal cardiac decelerations are seen during the first stage of labor it seems advisable to look for factors such as umbilical cord compression and decrease of materno-placental perfusion rather than fetal head compression.

Gas values of umbilical cord blood were investigated in 85 home deliveries and compared to 28 primiparous and 57 multiparous matched controls deliveries in the hospital. Controls were matched for age, parity, absence of medical indications for hospital delivery, administrations of drugs, spontaneous labor and delivery, duration of second stage and birth weight percentile. This control group was continuously monitored (fetal cardiotachogram, microblood investigation). The median values for pH in the umbilical artery (7.19) and base excess (-9.9 mmol/liter) in home deliveries differed significantly (p less than 10(-4)) from those of matched controls (7.25 and -7.7, respectively) delivered in the hospital. Similar differences were noted for umbilical venous blood values. It appears that delivery in the hospital with continuous fetal monitoring favors the birth of less acidotic children. Other variables, like the conduct of labor, episiotomies and supine position, have to be investigated in separate trials.

The preejection period (PEP) of the fetal cardiac cycle was studied in the chronically instrumented fetal lamb. An inflatable cuff occluder was positioned around the maternal common internal iliac artery, the pregnant ewe's main uterine blood-supplying vessel. Occlusion of the maternal common internal iliac artery produced a fall in pO2 and pH and a rise in pCO2. Fetal arterial blood pressure increased and PEP shortened, especially in the longer lasting occlusions. Fetal heart rate exhibited a bradycardia also during this type of occlusion. The fetal lamb's cardiovascular adjustments to biochemical changes caused by occlusion of the maternal uterine blood supply appear to be determined during the initial phase of occlusion by a chemoreceptor reflex-induced peripheral vasoconstriction mediated by the adrenergic nervous system. The condition is comparable to the one observed during the second part of the umbilical cord occlusions. The interaction between a supersensitive fetal myocardium and the adrenal release of catecholamines may play a dominant role during the second part of occlusion in the longer lasting experiments. Increase in peripheral resistance in the course of redistribution of blood flow during hypoxemia induces a prolongation of the PEP in the early phase of occlusion; overriding of this effect by an increase in myocardial contractility due to rising levels of adrenal catecholamines abbreviates the PEP in the later part of the longer lasting occlusions.

The distribution of gas values of umbilical cord blood was studied in an university clinic population during a period of 3 yr. All patients in labor were guided by obstetrical personnel and continuous electronic fetal monitoring (CTG). Microblood analyses were performed on indication of the CTG. The tenth percentile for the total population for umbilical artery blood pH was 7.14 and base excess was -12.7 mmol/l. The tenth percentile for pH in umbilical venous blood was 7.23 and base excess was -10.2 mmol/l. Increase of acidemia was seen in the following order: optimal pregnancy and labor, spontaneous vertex delivery, multiparity, primiparity, instrumental and breech delivery. Percentiles of umbilical cord blood gases could serve as an index for the standard of obstetrical care in addition to perinatal mortality and other measures of perinatal morbidity.

Aggregates of collagenase-dissociated neonatal rat heart cells have been tested for several membrane properties and shown to be comparable with cells from the intact heart. Action potentials, recorded from driven aggregates, are fully suppressed by tetrodotoxin (TTX). Under Mn2+, the plateau phase of the action potential disappears and no more mechanical activity can be detected. In aggregates, therefore, apparently both the fast sodium inward current and a slow inward current, which is at least partly carried by Ca2+ ions, contribute to the action potential. Pacemaker activity in spontaneously active aggregates is enhanced by adrenaline and slowed down by acetylcholine. Adrenaline also increases the plateau phase amplitude of the action potential and thereby the rate of repolarization. Acetylcholine shortens the action potential duration and increases the resting membrane potential. The electrical coupling between the cells in the aggregates is so tight that the aggregate seems to behave passively, like a single cell. It is concluded that aggregates of collagenase-dissociated neonatal rat heart cells may be used to study active electrical properties using the voltage clamp technique.

The pathways along which the electrical currents generated by the fetal heart are conducted to the surface of the maternal abdomen are not known. As a consequence, in recording the fetal electrocardiogram (FECG) it is hard to predict where electrodes should be placed in order to obtain an optimal signal. The amplitude of the FECG varies with gestation, and there is a large interindividual variability in the amplitude of the FECG and in the optimal recording site among subjects within the same gestational age. Attempts have been made to explain these phenomena in terms of volume conduction. In this research the complete potential distribution on the maternal abdomen is studied in connection with the geometrical configuration of the electrical source (fetal heart) and the volume conductor (surrounding tissues). For a small group of pregnant women the abdominal FECG is recorded simultaneously in 32 leads during a period of about one minute, once every two weeks from 20 weeks of gestation onwards. A spatial filtering technique which combines information of all 32 leads is used to provide a trigger of the fetal QRS complexes. Using this trigger, an average fetal complex is constructed for each lead by time coherent averaging, after subtraction of the maternal contribution. These average fetal complexes are combined to plot the complete potential distribution generated by the fetal heart at the maternal abdomen (fetal body surface map, FBSM) at any given time instant during the fetal cardiac cycle. At these recording sessions the geometry is carefully quantified by making transverse scans every 2 cm with a compound echo scanner. The contours of fetal head and body, the placenta and the uterus are manually drawn on hardcopies of the video display images. Real time echoscopy is used to support the identification of the geometry. The contours are fed into a computer using a graphics tablet. The three dimensional surfaces of fetus, placenta and uterus are separately represented by a triangulation of the respective contour lines. Figures 5 and 6 show an example of the triangulated representation of the recorded geometry. Figure 7 shows the average fetal complexes of an individual at 26 weeks of gestation, plotted at the site where they have been recorded.(ABSTRACT TRUNCATED AT 400 WORDS)

Perinatal data on 76 twin pregnancies demonstrated a significantly (P less than 0.01) lower Apgar score and acidemia in the umbilical artery for the second twin. Factors such as female sex, prematurity, low birth-weight and instrumental delivery accounted for this difference (P less than 0.05 or P less than 0.01). These differences were not found for parity, pregnancy complications and time interval. Using electronic fetal surveillance, expert personnel and rapid resuscitation the neonatal depression could be reversed rapidly, as demonstrated in capillary heel blood. Perinatal mortality was 2-3-times higher than for singletons but perinatal morbidity fell in the range for singletons and was not due to the short-lasting asphyxia during birth.