Jelte de Haan

Follicle growth curves and hormonal patterns in patients with the luteinized unruptured follicle syndrome

A prospective longitudinal and standardized study is presented, dealing with ultrasonographic and hormonal characteristics of the luteinized unruptured follicle (LUF) syndrome. Among 600 cycles monitored in 270 infertility patients, 40 cycles in 27 patients showed no evidence of follicle rupture, in spite of signs of luteinization, as reflected by basal body temperature recordings and progesterone determinations. In this study, 20 LUF cycles in 20 infertile patients were compared with 45 ovulatory cycles in 45 control women. During the follicular phase, no substantial difference in follicle growth was found, but after the luteinizing hormone peak, LUF follicles, instead of rupturing, showed a typical accelerated growth pattern. Both mean luteinizing hormone peak levels and midluteal progesterone levels were significantly lower in LUF cycles than in the control cycles. However, the duration of the luteal phase was not affected. Both central and local factors can be held responsible for the lack of follicle rupture. Ultrasound offers new possibilities as a noninvasive method in diagnosing the LUF syndrome.

Tumor angiogenesis: An independent prognostic parameter in cervical cancer

OBJECTIVE The purpose of this study was to investigate whether the intensity of tumor angiogenesis, expressed as microvessel density, is a parameter predicting the probability of lymph node metastasis and survival in patients with cervical cancer stages IB and IIA. STUDY DESIGN In a retrospective study of 114 patients with cervical cancer stages IB and IIA, microvessel density, lymph node status, and several other prognostic parameters were correlated with disease-free survival by a multivariate analysis according to Cox proportional-hazards model. RESULTS There was a significant difference in mean microvessel density between tumors with and without pelvic lymph node metastasis (p = 0.002). Both microvessel density (vessels per square millimeter of stroma). (p = 0.05) and pelvic lymph node metastasis (p = 0.007) correlated significantly and independently with disease-free survival. CONCLUSION This study demonstrates that microvessel density is an independent prognostic parameter for disease-free survival in patients with cervical cancer stages Ib and IIa.

Effects of asphyxia on the fetal lamb brain

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.

Analysis of heart rate and beat-to-beat variability: Interval difference index

The relationshp between the RR interval length (RR) and the RR interval-to-interval differences (RR differences) was investigated. Data on heart rate were obtained from 11 newborn infants in well-defined behavioral states undergoing polygraphy. It was found that the RR differences were strongly dependent on the RR interval length in all behavioral states. The relationship between the RR differences (y) and the interval length (RR) could be described by the equation y = alpha (RR-320)1.5 for the interval length in the investigated range from 375 to 605 msec. On the basis of this relationship the interval difference index (ID index) was constructed for the quantification of beat-to-beat heart rate variability. The ID index showed good independence from the long-term irregularity index (LTI index). Other statistical parameters proposed for the quantification of beat-to-beat heart rate variability are discussed and compared with the ID index.

Heart rate as an indicator of the behavioral state: Studies in the newborn infant and prospects for fetal heart rate monitoring☆☆☆

Term healthy newborn infants underwent polygraphy between days 4 and 6 of life. Behavioral states were determined according to Prechtls criteria. The neonatal heart rate was analyzed for the various behavioral states, with the use of quantitative indices for long-term and short-term irregularity. The applied indices were, respectively, the long-term irregularity index (LTI index) and the interval difference index (ID index). During state 1 the R-R interval length was longer (p less than 0.01), the LTI index lower (p less than 0.01), and the ID index higher (p less then 0.02) than in the immediately preceding or following state 2. For nonconsecutive states 1 and 2 a maximum separation was obtained with the discriminant function 0.0159 RR - 0.065 LTI + 0.062 ID - 7.49. This discriminant function gave a total percentage of correct classification of states 1 and 2 epochs of 93%. The data are discussed with respect to the presence of cycling sleep states in the newborn infant as well as in the fetus. Prospects for fetal antepartum heart rate monitoring are considered.

p53 tumor suppressor gene protein expression in cervical cancer: relationship to prognosis

OBJECTIVE Mutation of the p53 gene can be found in several human tumors. We tested the hypothesis whether overexpression of p53 protein is a parameter of more aggressive disease in patients with cervical cancer. STUDY DESIGN In this study, we describe the effects of p53 overexpression in 156 patients with cervical cancer (Figo stage IB-IV) by assessing expression patterns of the p53 gene product using a monoclonal anti-p53 antibody (DO7). RESULTS Overexpression of p53 tumor suppressor gene protein was observed in 30.2% of the tumors, low expression in 30.7% and 39.1% of the tumors showed no p53 immunoreactivity. With increase in stage, p53 overexpression raised from 20.1% in stage IB to 60% in stage IV. A significant correlation between p53 overexpression and disease-free survival of patients was observed, however, after stratification for stage, this effect disappeared. CONCLUSIONS The p53 mutation expressed as p53 tumor suppressor gene protein overexpression is a late event in cervical cancer genesis and does not appear to be of prognostic significance in cervical cancer.

Umbilical Artery Pulsatility Index and Placental Vascular Resistance during Acute Hypoxemia in Fetal Lambs

The effect of hypoxemia on the pulsatility index (PI) of the umbilical artery flow velocity waveform and placental vascular resistance was studied. Fetal hypoxemia was induced by maternal breathing of a low-oxygen gas mixture. Umbilical venous blood flow was measured with an electromagnetic flowmeter. Placental vascular resistance (PVR) was defined as the ratio perfusion pressure (mean arterial pressure minus umbilical venous pressure) and umbilical blood flow. Umbilical artery velocity waveforms were obtained by a 5-MHz pulsed Doppler device around one umbilical artery in 4 lambs and by a transcutaneous 4-MHz continuous wave Doppler transducer in 3 lambs. Fetal arterial oxygen content was lowered from 2.28 +/- 0.18 to 0.93 +/- 0.15 mM (p less than 0.05), while pCO2 and pH remained unchanged. Control values of the hemodynamic variables were compared with values during deepest hypoxemia. Fetal heart rate, mean arterial and umbilical venous pressure, PVR and the umbilical artery PI did not significantly change, whereas umbilical blood flow increased from 436 +/- 64.7 to 491 +/- 65.9 ml/min (p less than 0.05) during deepest hypoxemia. Individual regression analysis, however, showed a significant inverse correlation of umbilical venous pressure whereas PVR had a positive correlation with actual oxygen content. It is concluded that acute fetal hypoxemia slightly decreases PVR, but does not affect the umbilical artery PI in sheep. Decreasing fetal oxygenation is associated with an increase in pressure in the umbilical vein.

EFFECTS OF SURGERY AND ASPHYXIA ON LEVELS OF NUCLEOSIDES, PURINE BASES, AND LACTATE IN CEREBROSPINAL FLUID OF FETAL LAMBS

ABSTRACT: During severe oxygen shortage, the fetal brain resorts to anaerobic metabolism and AT? 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. 4) The rate of increase of ATP catabolites in CSF is higher in the nonsurviving animals and may therefore be predictive for fetal death.

The T/QRS ratio of the electrocardiogram does not reliably reflect well-being in fetal lambs

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.

Possible neuroprotective properties of flunarizine infused after asphyxia in fetal lambs are not explained by effects on cerebral blood flow or systemic blood pressure

ABSTRACT: 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.