Reduction of brain metastases in plasminogen activator inhibitor-1-deficient mice with transgenic ocular tumors.

Plasminogen activator inhibitor-1 is known to play a paradoxical positive role in tumor angiogenesis, but its contribution to metastatic spread remains unclear. We studied the impact of plasminogen activator inhibitor (PAI)-1 deficiency in a transgenic mouse model of ocular tumors originating from retinal epithelial cells and leading to brain metastasis (TRP-1/SV40 Tag mice). PAI-1 deficiency did not affect primary tumor growth or vascularization, but was associated with a smaller number of brain metastases. Brain metastases were found to be differentially distributed between the two genotypes. PAI-1-deficient mice displayed mostly secondary foci expanding from local optic nerve infiltration, whereas wild-type animals displayed more disseminated nodules in the scissura and meningeal spaces. SuperArray GEarray analyses aimed at detecting molecules potentially compensating for PAI-1 deficiency demonstrated an increase in fibroblast growth factor-1 (FGF-1) gene expression in primary tumors, which was confirmed by reverse transcription-polymerase chain reaction and western blotting. Our data provide the first evidence of a key role for PAI-1 in a spontaneous model of metastasis and suggest that angiogenic factors, such as FGF-1, may be important for primary tumor growth and may compensate for the absence of PAI-1. They identify PAI-1 and FGF-1 as important targets for combined antitumor strategies.

Homozygous deletion in the coding sequence of the c-mer gene in RCS rats unravels general mechanisms of physiological cell adhesion and apoptosis.

The RCS rat presents an autosomal recessive retinal pigment epithelium dystrophy characterized by the outer segments of photoreceptors being phagocytosis-deficient. A systematic genetic study allowed us to restrict the interval containing the rdy locus to that between the markers D3Mit13 and D3Rat256. We report the chromosomal localization of the rat c-mer gene in the cytogenetic bands 3q35-36, based on genetic analysis and radiation hybrid mapping. Using a systematic biocomputing analysis, we identified two strong related candidate genes encoding protein tyrosine kinase receptors of the AXL subfamily. The comparison of their expression patterns in human and mice tissues suggested that the c-mer gene was the best gene to screen for mutations. RCS rdy- and RCS rdy+ cDNAs were sequenced. The RCS rdy- cDNAs carried a significant deletion in the 5' part of the coding sequence of the c-mer gene resulting in a shortened aberrant transcript encoding a 20 amino acid peptide. The c-mer gene contains characteristic motifs of neural cell adhesion. A ligand of the c-mer receptor, Gas6, exhibits antiapoptotic properties.

Prediction of difficult vaginal birth and of cesarean section for cephalopelvic disproportion in early labor.

OBJECTIVE: A total of 1,692 patients were evaluated in early labor, and predictions were made for easy labor-vaginal birth, difficult labor-vaginal birth, or improbable vaginal birth-cesarean section. METHODS: The prediction was based on clinical evaluation of pelvic dimensions, and fetal measurements by sonography at term. RESULTS: The combined prediction that a patient would have either a difficult labor-vaginal birth or cesarean section was very accurate (362 out of 370, or 97.8%). However, the separate prediction of difficult labor-vaginal birth and a cesarean section was less accurate, although still significant (73.4% and 90.2%, respectively). A similar study on 141 vaginal birth after cesarean (VBAC) candidates showed that by sectioning electively patients in whom cesarean sections were predicted, the cesarean section rate barely increased. CONCLUSION: Careful evaluation of a patient in early labor could help to recognize the dystocic labor-delivery and early indication for cesarean sections. This would avoid unnecessary and prolonged labor without necessarily increasing the cesarean section rate.

Prominent neuronal-specific tub gene expression in cellular targets of tubby mice mutation.

The tubby strain of mice exhibits maturity-onset obesity and sensory deficits in vision and hearing. The mutated gene, tub , responsible for this phenotype was identified recently, but the function of the TUB protein has not been deduced from its amino acid sequence. This prompted us to undertake expression mapping studies with the hope that they might help to elucidate the biological role of the TUB protein. We report the tub gene expression pattern in embryonic, fetal and adult mice tissues as determined by northern blots and in situ hybridization, using antisense oligonucleotidic probes. In mouse embryos, tub is expressed selectively in differentiating neurons of the ensemble of central and peripheral nervous systems, starting at 9.5 days after conception. In adult mice, tub is transcribed in several major brain areas, including cerebral cortex, hippocampus, several nuclei of the hypothalamus controlling feeding behavior, in the spiral ganglion of the inner ear and in the photoreceptor cells of the retina. These structures contain potential cellular targets of the tubby mutation-induced pathogenesis. The neuronal-specific tub gene distribution allows the establishment of a genotype-phenotype correlation in the tubby mice. This correlation is reminiscent of that observed in fat/fat mice, whose phenotype, also characterized by obesity, is caused by a null mutation in the carboxypeptidase E (CPE) gene. Our observations highlight similarities between CPE, prohormone convertases, several neuropeptides and tub gene expression patterns during embryogenesis, and may narrow down the avenues to explore in order to determine ultimately the function of the TUB protein.

Effect of modern obstetrics on mothers from Third-World countries.

Mothers born and raised in third-world countries compared to women born in the United States are on average of shorter size, have less weight, have narrower pelvic dimensions, and give birth to smaller infants without much difficulty. This may be due to a low-protein diet and inadequate prenatal care. Those mothers who were born and raised outside the United States (therefore with narrow pelvic dimensions), but who eat a high-protein diet and receive adequate prenatal care after migrating as adults to the United States, give birth to relatively large infants. This results in a marked cephalopelvic disproportion and severe dystocia, which frequently leads to cesarean birth. It appears that nutritional factors during pregnancy and infancy play a role as important as genetic factors in the etiology of cephalopelvic disproportion.

The shapes of the female pelvis. Contributing factors.

OBJECTIVE: To determine the etiologic factors that play a role in shaping the female pelvis. STUDY DESIGN: The backgrounds of 611 pregnant women at term who underwent x-ray pelvimetry between 1962 and 1980 at term were extensively investigated. RESULTS: Several facts were statistically significant. First, 24.1% of the patients had an android pelvis, although only 5.7% presented any sign of hyperandrogenism. Signs of hyperandrogenism were similarly encountered in patients with a gynecoid and any other type of pelvis. Second, the android pelvis was encountered mostly in patients exposed to strenuous physical activity during adolescence. Third, the anthropoid pelvis was encountered more often when the acquisition of erect posture was delayed beyond the usual age of 14 months, while a platypelloid pelvis was more frequent when erect posture was acquired before 14 months. CONCLUSION: The final shape of the female pelvis seems to be determined by culture and environment as well as by genetics.

Reconstruction of the STS 14 (Australopithecus africanus) pelvis.

The study reports a reconstruction of the sacrum in STS 14 based on extrapolation from the measurements of the first two sacral vertebrae of STS 14 and of the angle formed by the anterior surfaces of their vertebral bodies. Reconstruction is based on comparisons of, and extrapolation from, sacra of Pan troglodytes, Homo sapiens, and Australopithecus afarensis. The reconstructed sacrum has an anterior sacral curvature of 39 degrees. The two ossa coxae were also completed by mirror imaging of one side by the other. With the pelvis completely reconstructed, the pelvic dimensions for the antero-posterior (AP) diameters of the pelvic inlet, midpelvis, and pelvic outlet are 85, 68, and 69 mm and the corresponding transverse (TR) diameters are 109, 88, and 103 mm, respectively. The posterior sagittal diameters in the three pelvic planes are small compared to the anterior sagittal diameters. This analysis indicates that the STS 14 pelvis is platypelloid in the three pelvic planes; i.e., all the AP diameters are smaller than the corresponding TR diameters. This makes the STS 14 pelvis similar to that of Al 288-1, save for a less pronounced degree of platypelloidy at the inlet in the former.

Growth of the fetus in the abdominal cavity.

The ratio pelvic/abdominal cavity is 6.9% in samples of nonhuman mammals and nonhuman primates, and rises to approximately 30% in humans. This relative reduction of the abdomen and increase of the pelvis is associated with a partial or total shift of some organs from the abdomen to the pelvis: rectosigmoid colon, bladder, and genital organs, which are mostly abdominal in quadrupeds and are mostly pelvic in humans. Pregnancy, always abdominal in nonhumans, is pelvic during the first trimester and becomes abdominal later on in humans. Near term the pregnancy expands easily in nonhumans in view of relatively small fetus and relatively large abdominal cavity. But, for the opposite reasons (large fetus, small abdomen), the human pregnancy is limited space-wise during its abdominal expansion. Unlike that of nonhumans, human pregnancy is faced with multiple problems. These include: 1) "squeezing" between the anterior abdominal wall and the lordosis of the lumbar spine; 2) compression of the aortocaval vessels; and 3) forward expansion of the abdomen resulting in reorientation of the trunk during erect posture as the pregnant woman approaches term. All these conditions are responsible for numerous pathological entities that occur during human pregnancy and are almost unknown in nonhuman mammals.

Umbilical waveform variations in the acutely distressed fetus: an experimental model in the fetal sheep.

In previous experimental studies on the pregnant ewe, umbilical arterial and venous waveform variations, produced by maternal aortic and umbilical cord occlusions of different degrees, were investigated in healthy fetuses (pH > 7.30). In our study, the fetal pH in 10 pregnant ewes was first brought down to below 7.20 with a preliminary series of maternal aortic and umbilical cord occlusions; then the 10 ewes were again submitted to a similar series of maternal aortic and umbilical cord occlusion. There were 24 experimental sessions with series of umbilical occlusions and 27 sessions with maternal aorta occlusions. The differences in waveform responses between these two types of fetuses are characteristic. The acidotic fetus produces more protracted drops in S, D, and venous velocity and, at the end of occlusion, the return to normal is slower with no reactive overflow waveform. In addition, there is a typical venous undulating pattern and no reappearance of blood flow velocity during the umbilical cord occlusion (always observed in healthy fetuses). Another important observation is that the fetal heart rate responses (bradycardia or tachycardia or no fetal heart rate variations) are more erratic in the acidotic fetus and do not relate to the intensity of the occlusion or to the fetal pH. The possible clinical implications of these experimental findings are discussed.

Vaginal birth after cesarean section: the patient's point of view.

Advocacy of vaginal birth after cesarean section (VBAC) is the current standard of care. We interviewed patients in our program about their attitudes toward VBAC and cesarean section. The success rate in our VBAC program is similar to rates reported in the literature (65 percent). However, interviews with our patients revealed that 40 percent had no desire to participate in the VBAC program, although they fulfilled the criteria for eligibility. The main reasons given for declining a trial of VBAC were the convenience of an elective cesarean section and fear of another prolonged, painful and potentially dangerous labor. Thirty-two percent of patients in whom VBAC was successful were dissatisfied with the experience and would have preferred an elective cesarean section. The reasons patients gave for attempting VBAC were different from the medical reasons proposed to them. The main reasons given were a desire to deliver "naturally," a fear of surgery and the concern that cesarean section might harm them or their baby.

Use of an indwelling Doppler probe to study acute changes in umbilical vein waveforms in the fetal sheep.

A chronic sheep model for Doppler umbilical vascular analysis with indwelling probes was used for the investigation of umbilical vein velocity waveforms. Maternal aortic occlusions produced a delayed drop but never eliminated umbilical vein velocity. With umbilical cord occlusion, there was immediate umbilical vein waveform response. Sudden cord occlusion and release showed reactive venous overflow velocity at the beginning and end of occlusion. Total cord occlusion produced zero velocity, but within seconds, the flow velocity was seen despite persistent occlusion in 65% of the cases. A characteristic undulating venous waveform pattern synchronous with fetal heart rate in over half of the cases was often observed. Reduction of blood flow by uteroplacental insufficiency may be differentiated from umbilical cord occlusion.

Intrauterine resuscitation in the severely distressed fetal dog.

Severe fetal distress was produced in 16 fetal dogs by successive and/or prolonged occlusion of the maternal abdominal aorta in an acute surgical preparation, and was characterized in fetal arterial blood of 7.06 for pH, 10 mm Hg for O2, 127 mm Hg for CO2, and fetal heart rate decelerations. Five fetuses recovered spontaneously in utero and delivered normally; 3 needed maternal oxygenation before delivery; 3 suddenly died in utero; 5 fetuses were delivered while still alive in utero when the tpH reached 6.85, and eventually expired. Intrauterine recovery and resuscitation was effective in some fetuses.

Ontogeny and evolution of pelvic diameters in anthropoid primates and in Australopithecus afarensis (AL 288-1).

Pelvic diameters (both anteroposterior [AP] and transverse [TR]) were investigated in a series of anthropoid primates. The ratio of diameters (AP/TR) in each of three pelvic planes (inlet, midpelvis, and outlet) was calculated. In addition to the above, the length of the iliac, pubic, and ischial axes and the angles between these axes were determined. The AP/TR ratio at the pelvic inlet is (reported in millimeters, +/- SD, unless otherwise specified) 1.81 +/- 0.27 in New World monkeys (Cebidae) and Macaca mulatta; 1.53 +/- 0.17 in hylobatids and pongids; 0.87 +/- 0.08 in Homo sapiens; and 0.58 in Australopithecus afarensis (AL 288-1). The AP/TR ratio in the midpelvis is 1.61 +/- 0.23 in nonhominid primates (Cebidae, M. mulatta, hylobatids, and pongids), 1.12 +/- 0.11 in humans, and 0.59 in AL 288-1. In monkeys (Cebidae and M. mulatta), hylobatids, pongids, H. sapiens, and AL 288-1, the ratios of the length of the pubic axis over the ischial axis were 0.84 +/- 0.06, 0.95 +/- 0.07, 1.10 +/- 0.15, and 1.46, respectively; the pubis-ilium angles were 96 +/- 11, 120 +/- 10, 131 +/- 11, and 147 degrees, respectively; and the ischium-pubis angles were 106 +/- 11, 86 +/- 8, 96 +/- 7, and 68 degrees, respectively. In none of these pelvic features was AL 288-1 "intermediate" between pongids and H. sapiens. The anatomical peculiarities of the pelvis in AL 288-1 are explained primarily as the result of early adaptation to erect posture, which resulted in the reduction of the distance between the sacroiliac joint and the hip joint. As a consequence, the sacral promontory moved toward the pubic symphysis, and this resulted in shortening of the AP diameter and widening of the TR diameter at the pelvic inlet.

The cephalopelvic disproportion index. Combined fetal sonography and x-ray pelvimetry for early detection of cephalopelvic disproportion.

The smallest pelvic diameter (either the anteroposterior of the inlet or the bispinal of the midpelvis) was determined with x-ray pelvimetry and compared to the biparietal diameter of the fetal head at term as determined with sonography. The difference between the two indicates how much wider the smallest diameter of the bony pelvis is than the fetal skull and was termed the cephalopelvic disproportion index. Vaginal delivery was impossible when the index was less than 9 mm and impossible or very difficult when between 9 and 12 mm. When it was greater than or equal to 13 mm, 26% needed a cesarean section, 19% had a difficult vaginal delivery, and the rest delivered vaginally with minimal or no difficulty. This technique clearly indicates when a vaginal delivery is impossible (index less than 9 mm) or very difficult (index less than 13 mm). The specificity was 100%. The index therefore can recognize, before labor, the cases of obvious cephalopelvic disproportion that contraindicate a trial of labor. It does not indicate, however, if a vaginal delivery is possible in the setting of a high index (sensitivity, 51%) because of the interference of other factors besides the cephalic and pelvic bony dimensions considered here. The index may prove most important in determining if a vaginal birth should occur after a cesarean section because it can clearly identify some patients who need a repeat cesarean section.

Sacral curvature and supine posture.

Sacral curvature (SC), represented by the angle between the first and the last sacral vertebrae, is a feature that differentiates the human pelvis from that of other animals. The sacral curvature was measured and studied in 14 cebids, 31 cercopithecids, 17 hylobatids, 85 pongids, 23 normal human children, 15 children with orthopedic handicaps, 49 normal adult human males, and 64 normal adult human females. Sacral curvature was minimal to nil in monkeys (mean 11.5 +/- 6 SD degrees), and moderate in apes (hylobatids, mean 16 +/- 10 SD degrees; pongids, mean 27.2 +/- 16 SD degrees). In human newborns SC is minimal, increasing progressively until adolescence, reaching a mean of 64.7 +/- 29 SD degrees in adult humans. This study investigates the different factors contributing to the formation of the sacral curvature. These factors include 1) the effect of erect posture, which tilts the upper part of the sacrum dorsally and the lower part of the sacrum ventrally, and 2) the influence of supine posture, which affects the development of the lower part of the sacrum. In addition to supine posture the levator ani, which is well developed in Homo sapiens, also affects the lower part of the sacrum and coccyx and influences its ventral orientation. Variation in SC can result from differences in onset and frequency of supine posture. This is the first time that supine posture has been shown to play a role in shaping the human pelvis, although it is as characteristic of H. sapiens as is erect posture.

The use of an indwelling Doppler probe to study acute changes in umbilical artery waveforms in the fetal sheep.

A chronic sheep model for Doppler umbilical vascular analysis was developed, in which indwelling Doppler probes were used. These were designed with a fixed angle of insonation and implanted directly on the umbilical cord to register umbilical artery velocity waveforms. The fetuses in eight pregnant ewes underwent maternal aortic and umbilical cord constrictions producing serial blood flow reductions. Occlusion of the umbilical cord and maternal aorta caused distinctly different waveforms. Cord occlusion produced an immediate response with an elevated systolic/diastolic ratio and disappearance of diastolic velocity. Maternal aortic occlusion produced a delayed response with drops in both systolic and diastolic velocity; diastolic velocity never reached zero. Although systolic/diastolic ratios are believed to reflect placental resistance, the maintenance of the systolic/diastolic ratio with diminution of systolic velocity suggests declining fetal cardiac output as an additional factor. It is possible to differentiate uteroplacental from umbilicoplacental insufficiency by Doppler methods. With technologic improvements Doppler ultrasonography may allow better analysis of acute stressful conditions during human labor.

Variations in blood supply allocations for quadrupedal and for bipedal posture and locomotion.

Hemodynamics and orthodynamics were investigated in quadrupeds (dogs) and in bipeds (humans). The subjects were investigated at rest in supine or lateral posture, in quadrupedal and then in bipedal posture, and during locomotion. Quadrupedalism in humans was with subjects on their hands and knees. Bipedalism in dogs was on hindlimbs with the forelimbs held by a technician. Blood flow in the main arteries of the body (aorta, external and internal carotid, subclavian, and femoral) was measured by sonography. Positional variations between the main bones of the body were determined from X-rays. This study investigated the reallocation of blood supply to different regions of the body when it switches from quadrupedal to bipedal posture and locomotion. Compared with resting posture, the principal findings are 1) cardiac output shows a minimal increase for humans in bipedal stance and a noticeable increase for dogs as well as humans in quadrupedal stance; 2) quadrupedal stance in humans and dogs and bipedal stance in dogs require increased blood supply to the muscles of the neck, back, and limbs, while human bipedal stance requires none of these; 3) cerebral blood flow (internal carotid) in humans did not change as a result of bipedal posture or locomotion, but showed a noticeable drop in quadrupedal posture and an even further drop in quadrupedal locomotion. The conclusion is that erect posture and encephalization produced a noticeable readjustment and reallocation of blood flow among the different regions of the body: This consisted in shifting a large volume of blood supply from the musculature to the human brain.

Effect of posture and locomotion on energy expenditure.

Energy expenditure for human adults and infants and for dogs was measured in resting (supine or lateral) posture, in bipedal posture and locomotion, and in quadrupedal posture and locomotion. Variations in respiratory and heart rate and in body temperature were utilized in this comparative study. Oxygen consumption was also measured in human adults. In human adults, bipedal posture and locomotion were shown to be much less energy-consuming than corresponding quadrupedal posture and locomotion. The opposite was observed in adult dogs, where bipedalism was shown to be much more energy-consuming than quadrupedalism. In addition, this study demonstrated, for human adults in their natural erect posture, an energy expenditure barely higher than in supine or lateral resting posture, while the dogs in their natural quadrupedal stance, the energy expenditure is much higher than in their resting posture. With respect to energy, therefore, humans are more adapted to bipedalism than dogs to quadrupedalism. Human children, at the transitional stage between quadrupedalism and bipedalism, have high and almost equal requirements for all postures and locomotions. This demonstrates, in term of energy, their incomplete adaptation to erect behavior.

Fetal heart rate and transcutaneous monitoring during experimentally induced hypoxia in the fetal dog.

A model of impaired oxygen delivery, using an acute surgical preparation in the fetal dog, is described. Fetal heart rate, transcutaneous pO2 and pCO2, and tissue pH were simultaneously recorded during hypoxic episodes produced by a series of successive occlusions of the maternal abdominal aorta. Corresponding values were also determined in the arterial blood of the fetus. The following pathophysiologic sequence of events was observed: 1) a latency period with no changes; 2) a drop in pO2 which stabilized later at a lower pressure; 3) late fetal heart rate deceleration, the pattern of which was not related to the progressively deteriorating fetal condition; 4) a progressive increase in pCO2; 5) a progressive decrease in pH. Abnormal tissue values consistently preceded and were more adversely affected than corresponding blood values. This experimental model demonstrates first that late decelerations of the fetal heart rate are an early sign of fetal hypoxia and second that a fall in fetal blood pH, beyond that level normally seen during labor, occurs relatively late in this pathophysiologic sequence. Between these two, there are intermediary stages that could be continuously monitored in order to identify worsening fetal condition. Continuous tissue pH and transcutaneous pO2 and pCO2 recording may potentially be of significant clinical value.