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Objective: Our purpose was to investigate (1) the safety of fetal magnesium sulfate treatment and (2) possible beneficial effects on the brain during perinatal asphyxia.Study Design: In 20 chronically instrumented fetal lambs (gestational age 125.8 +/- 3.5 days) four total umbilical cord occlusions for 5 minutes were repeated at 30-minute intervals. Fetuses received either saline solution (n = 11) or magnesium sulfate (n = 9) as a bolus of 300 mg intravenously 2 hours before occlusions, followed by an infusion of 100 mg/hr until 1 hour after occlusions.Results: In the treated fetuses plasma magnesium levels rose from 0.85 +/- 0.20 to 2.23 +/- 0.40 mmol/ L. Occlusions induced asphyxia, associated with mortality; 4 of 11 fetuses in the control group versus 1 of 9 in the magnesium-treated group died (not significant). Fetal electroencephalographic activity decreased and cerebral impedance increased during occlusions. Maximum spike and seizure activity occurred 5 to 10 hours after asphyxia. Neuronal loss was primarily localized in the corpus striatum. Magnesium caused no alterations in blood pressure, heart rate, or cerebral and peripheral blood flow, nor did it influence electrophysiologic responses or neuronal loss.Conclusions: Administration of magnesium sulfate was safe but did not offer significant cerebral protection from asphyxia in the near-term fetal lamb. [ABSTRACT FROM AUTHOR]

Objective: Brief repetitive total umbilical cord occlusions were used to induce fetal asphyxia and to evaluate the interrelationships with hypotension and fetal heart rate decelerations.Study Design: In 21 chronically instrumented fetal lambs (gestational age 126.8 +/- 0.6 days), repetitive total umbilical cord occlusion was performed 1 out of 2.5 minutes (n = 7), 2 out of 5 minutes (n = 9), or not at all (shams, n = 5). Occlusions proceeded until fetal blood pressure was < 20 mm Hg or failed to recover to baseline before the next occlusion.Results: At the nadir of asphyxia pH (mean +/- SEM) was 6.84 +/- 0.02, base excess 23.1 +/- 1.0 mmol/L, and lactate 14.2 +/- 0.4 mmol/L. Two fetuses died. The pattern of fetal heart rate decelerations remained relatively consistent throughout the experiments. In contrast, after an initial phase of sustained hypertension a progressive fall in trough blood pressure occurred after approximately 15 minutes of occlusion. The blood pressure recovery time in almost all fetuses lengthened abruptly near the end of the occlusion series, at a variable metabolic threshold. This was accompanied by a significant delay in fetal heart rate recovery in only five fetuses.Conclusions: Fetal compromise presented with the development of hypotension, without change in the pattern of fetal heart rate response. These data illustrate the limited diagnostic value of fetal heart rate monitoring to identify the development of cardiovascular compromise associated with severe decelerations in the previously healthy fetus. [ABSTRACT FROM AUTHOR]

A 53-year-old woman was wheelchair-dependent and unable to work due to an extreme increase in abdominal circumference. Closer investigation revealed an ovarian tumour. A mucinous cystadenoma of the ovary weighing more than 20 kg was removed with laparotomy. A 63-year-old woman presented with postmenopausal haemorrhage. Morbid obesity and agoraphobia had prevented her from visiting a doctor earlier. She was eventually diagnosed with stage 1C grade III endometrial carcinoma, which was treated with surgery and vaginal brachytherapy. The incidence of gynaecological tumours is increased in patients with a high BMI. This association is stronger for endometrial carcinoma than for ovarian carcinoma. Obesity has a favourable influence on the histological grade of endometrial carcinoma, and is associated with lower-stage ovarian cancer. Surgery-related complications are more common in obese patients. Determining the optimal dose of adjuvant therapy is also problematic in obese patients.

Extensive abdominal infections with Actinomyces were diagnosed in two women aged 35 and 33 years respectively, who suffered from the nonspecific symptoms fever and abdominal pain. These infections occur more often in women with an intrauterine device. Development of an abdominal mass with ureter or bowel obstruction may cause hydronephrosis and mechanical ileus. The patients underwent a laparotomy and a double-J catheter was inserted, which could be removed later on (temporary stoma). Treatment included high-dose penicillin i.v. followed by oral amoxicillin. Both patients recovered. It may be difficult to establish this diagnosis: the first patient was diagnosed by histopathological examination, in the second Actinomyces had been found in a routine cervical smear a few years earlier.

In a 57-year-old woman ovarian cancer spread lymphogenically to the groin and suprapubic skin.

Objective: This study was undertaken to determine whether myocardial injury occurs after repeated intrauterine asphyxia., Study Design: Near-term fetal sheep with implanted instrumentation underwent either sham occlusions (n = 8) or repeated brief umbilical cord occlusions (n = 12) continued until the onset of severe (<20 mm Hg) or sustained hypotension. After 3 days of recovery, the fetal hearts were perfusion fixed., Results: Repeated umbilical cord occlusions led to a severe metabolic acidosis (pH, 6.84 +/- 0.09; lactate concentration, 14.1 +/- 1.5 mmol/L) with increasing hypotension during occlusions, which were terminated after 128 +/- 38 minutes. After the occlusions, the mean arterial pressure showed a delayed fall, which resolved after 12 hours. Ultrastructural examination showed evidence of subendocardial injury, with dilatation of sarcoplasmic reticulum, margination and clumping of nuclear chromatin, and mitochondrial swelling. The most severe morphologic changes, including electron-dense mitochondrial inclusions, were found in the fetuses with delayed recovery of the fetal heart rate after the final occlusion., Conclusion: Subendocardial injury occurs after severe repeated intrauterine asphyxia in the late-gestation fetus, and this may contribute to cardiovascular compromise and the development of late decelerations.

The aim of this study was to determine whether there is a relationship between changes in PR-RR correlation of the fetal ECG and progressive changes in fetal acid-base status and blood pressure (BP) during repeated umbilical occlusion. Chronically instrumented fetal sheep at 126.8+/-0.6 d (mean+/-SEM) were randomized to receive 1 min of total umbilical cord occlusion either every 5 min for 4 h (1:5 group; n=8), or every 2.5 min until BP fell <2.7 kPa (20 mm Hg) on two successive occlusions (1:2.5 group; n=8). The PR-RR correlation was determined in 5- or 2.5-min intervals. Umbilical cord occlusion caused variable decelerations with initial sustained hypertension. In the 1:5 group BP remained elevated throughout, and there was little change in acid-base status (pH=7.34+/-0.07, base deficit=1.3+/-3.9 after 4 h). In contrast, after the third occlusion the 1:2.5 group showed progressive hypotension during occlusions, and severe progressive metabolic acidemia (pH 6.92+/-0.1, base deficit 17.0+/-4.7 mmol/L after the last occlusion). In both groups, the PR-RR relationship switched from positive to negative with the onset of occlusions, then reverted to positive after a variable interval. In the 1:2.5 group later reversion of the PR-RR to positive was associated with earlier and more prolonged hypotension during the middle and end of the occlusion series (p < 0.001). We conclude that the initial switch to a negative PR-RR relationship during repetitive umbilical occlusion was due to a reflex-mediated response unrelated to fetal acidosis or hypotension. Both stable well compensated fetuses and severely hypoxic, hypotensive fetuses subsequently showed a positive PR-RR correlation.

The aim of this study was to determine whether asphyxia induced by clinically relevant, brief repetitive umbilical cord occlusions is associated with cerebral compromise. Chronically instrumented fetal lambs were studied at 126.5 +/- 2.8 d of gestation (mean +/- SD, term 147 d). Occlusions were performed 1 out of every 2.5 min (group I, n = 7), 2 out of every 5 min (group II, n = 9), or not at all (shams, group III, n = 5), and discontinued at a predetermined threshold of severe or persistent hypotension. After 58 +/- 8 and 24 +/- 2 occlusions, in groups I and II, respectively, the pH was 6.83 +/- 0.09, Pco2 9.52 +/- 1.4 kPa, base excess -23.5 +/- 3.7 mM, and lactate 14.1 +/- 1.6 mM. Two fetuses (out of group II) did not recover from the final occlusion. Ongoing asphyxia was associated with progressive suppression of the EEG, which occurred faster and with more epileptiform and spike activity in group II. Cortical impedance remained elevated for 15.0 +/- 4.0 and 11.5 +/- 4.4 h, for groups I and II, respectively (NS). Focal infarcts occurred in the parasagittal cortex, thalamus, and cerebellum, in 6 out of 14 surviving asphyxiated fetuses. Mild selective neuronal loss was observed in these regions in 13 out of 14 fetuses. Infarction was associated with a longer period of blood pressure below baseline levels, with more epileptiform activity, and with slower normalization of the EEG. In a paradigm mimicking birth asphyxia, histologic damage similar to that observed clinically was found. The results suggest that brief repeated insults interact, leading to cardiac compromise and cumulative cell membrane damage in the fetal cerebrum.

Objectives: The evaluation of the changes in the relationship of the PR interval and fetal heart rate during prolonged fetal compromise in sheep at levels of acidosis comparable to those seen during human fetal compromise and to see whether these changes are potentially of use in the detection of fetal distress., Study Design: A retrospective analysis of continuous fetal electrocardiogram recordings during graded fetal hypoxemia in 20 chronically cannulated fetal sheep was performed. Baseline recordings during normoxemia were compared with recordings during hypoxemia by use of Fisher's exact test and the Student t test., Results: Sixteen of the 20 cases could be used for final analysis. Twelve showed a statistically significant change from a predominantly negative relationship between the PR interval and the fetal heart rate during normoxemia to a predominantly positive relationship during hypoxemia. Two cases showed an obvious trend in the same direction, which was statistically not significant. In two other cases no change in the relationship was observed., Conclusion: A changing relation between the PR interval and the fetal heart rate is of potential use in the detection of fetal compromise.

During perinatal asphyxia several mechanisms aim to limit cerebral damage. However, when the degree of asphyxia passes beyond a certain threshold, brain damage is inevitable. This review focuses on the various factors determining the final cerebral outcome. Metabolic and biochemical events, such as the intracellular level of calcium, the formation of oxygen derived free radicals, the release of excitotoxic neurotransmitters and the interrelationship of these parameters are discussed. Furthermore, steps possibly useful to pharmacologic intervention aiming to reduce cerebral damage are presented.

Objective: Our purpose was to determine the diagnostic power of the T/QRS ratio of the electrocardiogram to predict fetal well-being., Study Design: In 47 fetal lambs (3 to 5 days after surgery, gestational age 123.5 +/- 3.0 days) asphyxia was induced by restriction of uterine perfusion. Fetuses were either pretreated with an adenosine transport inhibitor (n = 16) or a calcium channel blocker (n = 12) or served as controls (n = 19). Arterial oxygen content > or = 1.5 mmol/L or pH > or = 7.15 were chosen as limits for fetal well-being., Results: Arterial oxygen content was reduced from 3.3 (+/- 1.0) to 1.3 (+/- 0.5) mmol/L, and pH decreased to 7.03 (+/- 0.10). Mortality was 53%. Both drugs did not affect well-being, survival, or the T/QRS ratio. Maximum T/QRS ratios were reached at the peak of asphyxia. Sensitivity and specificity of the T/QRS ratio were 24.0% and 42.6% to predict hypoxemia and 25.1% and 45.3% to predict acidemia. Pearson correlation coefficients for T/QRS ratio versus oxygen content and pH were 0.169 and 0.192, respectively., Conclusions: (1) In fetal lambs the T/QRS ratio failed to predict hypoxemia or acidemia. (2) Fetal survival was not correlated with the height of the T/QRS ratio during or after asphyxia.

During severe oxygen shortage, the fetal brain resorts to anaerobic metabolism and ATP becomes catabolized. High levels of nucleosides, hypoxanthine, and xanthine (ATP catabolites) in cerebrospinal fluid (CSF) may therefore be associated with increased neonatal neurologic morbidity. In 22 fetal lambs (3 to 5 d after surgery, gestational age 123.5 +/- 3.5 d), arterial oxygen content was progressively reduced to 35% of the baseline value with a balloon occluder around the maternal common internal iliac artery. This resulted in a 1-h period of asphyxia, leading to a pH of 7.02 +/- 0.03 and a base excess of -17.0 +/- 1.0 mM. Mortality was 50%. CSF was sampled from the spinal cistern and analyzed using HPLC. During reoxygenation, hypoxanthine and xanthine may serve as substrate for xanthine oxidase with concomitant production of oxygen-derived free radicals, which may aggravate cerebral damage. The main difference between surviving and nonsurviving animals was the speed of increment of ATP catabolites in CSF: in the surviving group levels increased steadily, recovery values being significantly elevated compared with asphyxia values, whereas in the nonsurviving group the rise was rapid and levels during asphyxia did not differ significantly from levels during recovery. We conclude that 1) catheterization of the spinal cistern leads to increased levels of CSF hypoxanthine, xanthine, and inosine, and 2) during fetal asphyxia, levels of these ATP catabolites and lactate in CSF increase. 3) Maximum levels are reached during the recovery period and are similar for surviving and nonsurviving animals, but during asphyxia CSF levels of hypoxanthine and lactate were higher in the nonsurviving fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

The strength of the fern test to differentiate between amniotic and nonamniotic fluid in vaginal discharge was determined in 51 term women in labor with ruptured membranes and compared with that in a group of 120 nonlaboring subjects, presenting with nonspecific vaginal fluid loss. Sensitivity and specificity in the laboring group were 98.0 and 88.2%, respectively, in agreement with previous reports. In contrast, in the non-laboring group sensitivity and specificity were only 51.4 and 70.8%, respectively. The result of the fern test predicted the actual state of the membranes correctly in 63% and incorrectly in 29% of these patients. In 16 or 39 subjects with ruptured membranes (approximately 40%), the outcome of the fern test was negative. The modest diagnostic strength of the fern test in the present study compared with previously reported data is at least in part due to differences in study population (laboring versus nonlaboring) and to the fact that observers were deprived of relevant clinical information. It is concluded that the fern test should be granted supportive rather than conclusive value in diagnosing ruptured membranes in nonlaboring women presenting with nonspecific vaginal fluid loss.

Objective: Our purpose was to study the effect of fetal asphyxia on the release of hypoxanthine and xanthine in cerebrospinal fluid and on brain histologic characteristics., Study Design: In seven fetal lambs (3 to 5 days after surgery, gestational age 124.3 +/- 2.6 days) asphyxia was induced by restriction of uterine blood flow., Results: Fetal pH and base excess were reduced to 6.99 +/- 0.02 and -17.6 +/- 0.9 mmol/L, respectively. Cerebral blood flow increased during asphyxia and returned to normal in the recovery phase. Maximum concentrations of cerebrospinal fluid hypoxanthine and xanthine were reached in the normoxemic recovery phase. This high level of substrates during normoxemia facilitates oxygen free radical formation and may thus aggravate postasphyctic brain damage. Histologic evaluation of the brain 3 days after the insult showed a variable degree of edema. Coagulative neuronal changes, characteristic of irreversible cell death, were only occasionally detected. These changes were most obvious in the Purkinje cells of the cerebellum., Conclusions: Fetal asphyxia induced by uterine blood flow restriction is associated with high levels of cerebrospinal fluid hypoxanthine and xanthine in the recovery phase. Microscopically detectable brain damage, although not extensive, is mainly located in the cerebellum.

Neuroprotective properties of the calcium channel blocker flunarizine have been reported after hypoxic-ischemic insults in immature, infant, and adult rats. However, its effect on fetal regional cerebral blood flow (rCBF) and systemic blood pressure after severe asphyxia is not known. In 15 fetal lambs (3 to 5 d after surgery; gestational age at the experiment, 123.2 +/- 2.5 d), arterial oxygen content was progressively reduced to 30% by restriction of uterine blood flow with an inflatable balloon occluder around the maternal common internal iliac artery. The rCBF was measured with radioactive microspheres at baseline condition, after 1 h of severe asphyxia, and at 30 and 120 min in the recovery phase. Immediately after the end of the occlusion period, fetuses randomly received either flunarizine or its solvent (0.5 mg/kg estimated fetal weight). No differences in rCBF changes between groups were observed during and after asphyxia. Changes in arterial blood pressure or fetal heart rate due to flunarizine could not be demonstrated either. Only five fetuses (33%) survived this degree of asphyxia longer than 24 h: four of the flunarizine-treated group and one of the control group. It is unlikely that this possible protective property of the drug is caused by its influence on rCBF, arterial blood pressure, or fetal heart rate in the phase immediately after asphyxia.

When the energy demand exceeds the energy supply, anaerobic metabolism takes over and the ATP catabolite adenosine is generated. Adenosine acts as a coronary vasodilator, thereby increasing the oxygen supply to the heart. Its potential, however, is poorly exploited due to extensive catabolism. R-75231 inhibits transport of adenosine into endothelial cells, where it is catabolized, resulting in an elevation of interstitial adenosine concentrations. In 14 fetal lambs (3 to 5 d after surgery, gestational age 124.1 +/- 1.1 d), seven fetuses were pretreated with R-75231 (0.1 mg/kg estimated fetal weight as a bolus injection in the inferior vena cava), whereas the other seven served as controls. After 1 h of severe asphyxia, induced by restriction of uterine blood flow, those fetuses treated with R-75231 showed a faster normalization of aortal pH and, in contrast to the control group, did not develop tachycardia. The percentage increase in myocardial blood flow during asphyxia, measured with radioactive microspheres, was significantly higher in the R-75231-treated group compared with the control group (437 and 284%, respectively). In the control group, only three fetuses recovered and survived, whereas in the R-75231 group, all seven animals recovered after severe asphyxia. It is concluded that fetal lambs pretreated with R-75231 before the onset of severe asphyxia have an enhanced increase in myocardial blood flow during asphyxia, recover faster, and survive longer.

Through the developments in molecular biology the interest for large scale animal cell cultivation has sharply increased during the last 5 years. At our laboratory, four different cultivation systems were studied, all of which are homogeneous culture systems, as they lend themselves best for scaling up and for the control of culture conditions. The four different systems which were compared are: batch culture, continuous chemostat, continuous recycling and continuous perfusion culture system, both for cells growing in suspension and for anchorage dependent cells in microcarrier culture. Our results indicate that for the production of virus vaccines and cells the batch and recycling culture system are most suitable. Disadvantages of the continued chemostat culture system are: the system is only applicable for cells growing in suspension; relatively low concentrations of cells and cellular products are obtained. The continuous perfusion system appears to be very suitable for the production of cellular components and also for the production of viruses which do not give cell lysis.