Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models.

BACKGROUND: The role of the microbiome has become synonymous with human health and disease. Bile acids, as essential components of the microbiome, have gained sustained credibility as potential modulators of cancer progression in several disease models. At physiological concentrations, bile acids appear to influence cancer phenotypes, although conflicting data surrounds their precise physiological mechanism of action. Previously, we demonstrated bile acids destabilised the HIF-1α subunit of the Hypoxic-Inducible Factor-1 (HIF-1) transcription factor. HIF-1 overexpression is an early biomarker of tumour metastasis and is associated with tumour resistance to conventional therapies, and poor prognosis in a range of different cancers. METHODS: Here we investigated the effects of bile acids on the cancer growth and migratory potential of cell lines where HIF-1α is known to be active under hypoxic conditions. HIF-1α status was investigated in A-549 lung, DU-145 prostate and MCF-7 breast cancer cell lines exposed to bile acids (CDCA and DCA). Cell adhesion, invasion, migration was assessed in DU-145 cells while clonogenic growth was assessed in all cell lines. RESULTS: Intracellular HIF-1α was destabilised in the presence of bile acids in all cell lines tested. Bile acids were not cytotoxic but exhibited greatly reduced clonogenic potential in two out of three cell lines. In the migratory prostate cancer cell line DU-145, bile acids impaired cell adhesion, migration and invasion. CDCA and DCA destabilised HIF-1α in all cells and significantly suppressed key cancer progression associated phenotypes; clonogenic growth, invasion and migration in DU-145 cells. CONCLUSIONS: These findings suggest previously unobserved roles for bile acids as physiologically relevant molecules targeting hypoxic tumour progression.

Predicting carotid artery disease and plaque instability from cell-derived microparticles.

OBJECTIVES: Cell-derived microparticles (MPs) are small plasma membrane-derived vesicles shed from circulating blood cells and may act as novel biomarkers of vascular disease. We investigated the potential of circulating MPs to predict (a) carotid plaque instability and (b) the presence of advanced carotid disease. METHODS: This pilot study recruited carotid disease patients (aged 69.3 ± 1.2 years [mean ± SD], 69% male, 90% symptomatic) undergoing endarterectomy (n = 42) and age- and sex-matched controls (n = 73). Plaques were classified as stable (n = 25) or unstable (n = 16) post surgery using immunohistochemistry. Blood samples were analysed for MP subsets and molecular biomarkers. Odds ratios (OR) are expressed per standard deviation biomarker increase. RESULTS: Endothelial MP (EMP) subsets, but not any vascular, inflammatory, or proteolytic molecular biomarker, were higher (p < .05) in the unstable than the stable plaque patients. The area under the receiver operator characteristic curve for CD31(+)41(-) EMP in discriminating an unstable plaque was 0.73 (0.56-0.90, p < .05). CD31(+)41(-) EMP predicted plaque instability (OR = 2.19, 1.08-4.46, p < .05) and remained significant in a multivariable model that included transient ischaemic attack symptom status. Annexin V(+) MP, platelet MP (PMP) subsets, and C-reactive protein were higher (p < .05) in cases than controls. Annexin V(+) MP (OR = 3.15, 1.49-6.68), soluble vascular cell adhesion molecule-1 (OR = 1.64, 1.03-2.59), and previous smoking history (OR = 3.82, 1.38-10.60) independently (p < .05) predicted the presence of carotid disease in a multivariable model. CONCLUSIONS: EMP may have utility in predicting plaque instability in carotid patients and annexin V(+) MPs may predict the presence of advanced carotid disease in aging populations, independent of established biomarkers.

Genetic variability and rodent models of human aging.

Inbred strains, outbred strains, and natural populations of rodents differ greatly in the amount and nature of the genetic variability they possess. Consequently, as models of human aging they vary with respect to the areas of research to which they are best suited. Inbred strains, in which all individuals are genetically identical, are best suited as models of specific disease processes and for manipulations involving tissue transplantation. Their lack of genetic variability, however, and the disruption of genetic linkage groups that occurs during inbreeding limit their value as models of more general aging processes. Outbred strains exhibit large interindividual genetic variation--a result of ongoing random accumulation of deleterious alleles with late ages of action. This makes them ideal models for studying the diversity of pathologic lesions, connections between pathologies, and susceptibility to pathologic lesions that collectively produce the reductions in reproductive capacity, physiological efficiency, and viability that are characteristic of aging. Natural populations also may exhibit relatively large amounts of interindividual genetic variability. However, difficulties with husbandry, variable parasite loads, and complex population genetics can compromise their suitability as models of human aging. Ultimately, a consideration of the range of animal models available and a more careful matching of the goals of a study with the genetic system of the model will prove fruitful to gerontology.

Fetal heart rate decelerations during a nonstress test.

In a review of 2000 nonstress tests (NSTs) on 972 pregnant women at high risk at the authors' institution, 94 exhibited fetal heart rate (FHR) decelerations in response to fetal activity in 110 (46.6%) of the 236 NSTs. The NST results were interpreted as either reactive (178) or nonreactive (58). Of those cases with an FHR deceleration pattern, an abnormal cord position was observed in 55.3% (X2 = 68; P less than .001). Of the 74 patients who went into labor, 59.5% demonstrated variable FHR decelerations. Moreover, 8.5% required cesarean section for fetal distress. Of greater importance, 3 intrauterine fetal deaths occurred that appeared to be related to the abnormal cord position. FHR decelerations may occur during reactive as well as nonreactive NSTs. When FHR decelerations are present, they may signify some form of abnormal cord position and require further evaluation by ultrasonography and a contraction stress test.

Nonstress test and maternal serum glucose determinations.

Serum glucose levels were measured in 50 nondiabetic pregnant women between 33 and 43 weeks' gestation following a nonstress test (NST) to determine the relationship between maternal glucose levels and the results of the NST. Two comparable groups of 25 patients each were formed based on the NST results, reactive and nonreactive. Overall, maternal glucose level for the study population was 71.3 +/- 20.1 mg/dl. Although the difference was not statistically different, the nonreactive NST group did demonstrate slightly higher glucose levels (71.6 +/- 17.3 mg/dl) than did the reactive group (70.9 +/- 17.3 mg/dl). Furthermore, patients studied for suspected intrauterine growth retardation or who had a history of a prior stillbirth and significantly lower (P less than .025) glucose levels than those tested for other indications. These results suggest that there is no correlation between the NST results and maternal serum glucose concentrations in a nondiabetic population. The significantly lower maternal glucose levels observed in intrauterine growth retardation and prior stillbirth groups warrant further investigation.

Obstetric decision-making: responses to patients who request cesarean delivery.

The right of patients to be actively involved in treatment decisions is now widely accepted. A survey of 112 obstetricians was conducted to determine their responses to several cases in which a laboring woman asks for a cesarean section, even though the obstetrician has recommended a continued trial of labor/vaginal delivery. In 12 of the 19 cases there was substantial variation among respondents in the decision to agree with the patient. There was also no agreement, in many of these cases, on the presence or absence of a medical indication for abdominal delivery. The ethical aspects of this problem are explored.

The four-quadrant assessment of amniotic fluid volume: an adjunct to antepartum fetal heart rate testing.

Amniotic fluid volume assessment using a semiquantitative four-quadrant technique, the amniotic fluid index, was evaluated in relationship to fetal heart rate (FHR) testing and perinatal morbidity in 330 high-risk pregnancies. An inverse relationship was found between the amniotic fluid index and nonreactive nonstress tests (NST), FHR decelerations, meconium staining, cesarean section for fetal distress, and low Apgar scores. More important, adverse perinatal outcome was significantly more frequent with diminished compared with normal amniotic fluid volume, even if the NST was reactive.

Permanent Erb palsy: a traction-related injury?

Historically, the primary risk factor attributed to brachial plexus injury during birth has been excessive traction applied at delivery to an entrapped anterior shoulder. However, recent evidence has suggested that not all cases of brachial plexus palsy are attributable to traction. We have encountered several cases of permanent Erb palsy associated with birth that were not attributable to traction applied at delivery. We reviewed cases of neonates with documented permanent Erb palsy that occurred either in the absence of shoulder dystocia or in the neonate's posterior arm in the presence of anterior shoulder dystocia. We identified four cases that occurred in the absence of shoulder dystocia and four cases that occurred in the posterior arm of infants with anterior shoulder dystocia. These data further support the notion that the etiology of permanent brachial plexus palsy associated with birth may not be related to traction.

Uterine activity patterns in uterine rupture: a case-control study.

OBJECTIVE: To determine whether uterine activity patterns are associated with intrapartum uterine rupture. METHODS: Because of the infrequency of uterine rupture, a case-control design was implemented. Cases were women who sustained uterine ruptures during a trial of labor, resulting in a neurologically impaired neonate. Controls were women who had a successful vaginal birth after cesarean (VBAC) or vaginal delivery with no history of uterine scar. The uterine activity patterns of cases were compared with those of each control group for number of contractions per hour, uterine tetany (contraction longer than 90 seconds), and uterine hyperstimulation (five or more contractions in a 10-minute period). RESULTS: The final study population consisted of 18 rupture patients, 35 VBAC patients, and 33 spontaneous vaginal delivery patients. Women in the rupture group had fewer contractions per hour (15.8+/-7.3) than VBAC (19.7+/-5.5) (P < .05) or spontaneous delivery group (19.4+/-6.6) (P < .10). VBAC patients were five times as likely to have 16 or more contractions per hour than were rupture patients, 95% confidence interval [CI] 1.3, 21.3, P < .02). Patients who had spontaneous delivery were 3.5 times more likely to have 16 or more contractions per hour than were rupture patients (95% CI 0.9, 14.1, P = .08). The rupture group had equal or less uterine tetany than did the controls. CONCLUSION: Uterine activity patterns and oxytocin use do not appear to be associated with the occurrence of intrapartum uterine rupture.

Placenta previa/accreta and prior cesarean section.

To assess the relationship between increasing numbers of previous cesarean sections and the subsequent development of placenta previa and placenta accreta, the records of all patients presenting to labor and delivery with the diagnosis of placenta previa between 1977 and 1983 were examined. Of a total of 97,799 patients, 292 (0.3%) had a placenta previa. The risk of placenta previa was 0.26% with an unscarred uterus and increased almost linearly with the number of prior cesarean sections to 10% in patients with four or more. The effect of advancing age and parity on the incidence of placenta previa was much less dramatic. Patients presenting with a placenta previa and an unscarred uterus had a 5% risk of clinical placenta accreta. With a placenta previa and one previous cesarean section, the risk of placenta accreta was 24%; this risk continued to increase to 67% (two of three) with a placenta previa and four or more cesarean sections. Possible mechanisms and clinical implications are discussed.

Preeclampsia/eclampsia: hemodynamic and neurologic correlations.

Three patients with eclampsia and four with severe preeclampsia underwent pulmonary artery catheterization before either labor or significant volume infusion. There was no difference in systemic or pulmonary vascular resistance, cardiac index, left ventricular stroke work index, or any other hemodynamic parameters between the eclamptic and severely preeclamptic patients. Despite the small numbers, plasma colloid osmotic pressures were significantly lower in the eclamptic patients. Factors other than the intensity of peripheral vasospasm may primarily affect the occurrence of grand mal seizures in patients with preeclampsia.

An active management approach to the postdate fetus with a reactive nonstress test and fetal heart rate decelerations.

Reports have shown that a reactive nonstress test (NST) with decelerations in the postdate patient is associated with an increase in perinatal morbidity. Based on these observations, patients who exhibited this fetal heart rate (FHR) pattern during NST had labor induced. The purpose of this report was to determine what impact, if any, this approach had on subsequent maternal and fetal outcome. The pregnancy outcome of 470 patients who delivered during 1984 within seven days of their last NST was compared with data from this institution in 1980. The last NST was reactive in 420 patients (89.4%) and nonreactive in 50 (10.6%). Fetal heart rate decelerations occurred in 130 patients (27.7%); of these, 96 (73.9%) were reactive and 34 (26.1%) nonreactive. Postdate patients whose last NST was reactive with decelerations had similar outcomes to patients with a nonreactive NST on their last test, but less favorable outcomes than patients with reactive tests alone. Comparison with data from our institution in 1980 shows that prompt induction of labor in the postdate patient with a reactive NST and decelerations resulted in significantly lower perinatal morbidity, with no corresponding increase in maternal morbidity. These results lead us to conclude that a reactive NST without FHR decelerations is a reliable indicator of fetal well-being in the postdate pregnancy. However, in the postdate pregnancy with a reactive NST with FHR decelerations, induction of labor is indicated.

Fetal death following antepartum fetal heart rate testing: a review of 65 cases.

The nonstress test (NST) remains in widespread use for antepartum fetal surveillance. Our institutional experience with 14,028 patients and 38,645 tests over eight years reveals a fetal death rate of 2.6 per 1000 within seven days of a reactive NST. The autopsy findings of 53 fetal deaths are presented. The most common findings, in descending order of frequency, were meconium aspiration, perinatal infection, and abnormal umbilical cord position. These findings support changes we have made in our antepartum assessment protocols.

Continuing role of the nonstress test in the management of postdates pregnancy.

A retrospective analysis of 239 postdate patients who delivered within seven days of their last nonstress test between 1 July 1980 and 30 June 1981 was done to determine whether or not there was a relationship between variable fetal heart rate (FHR) decelerations, a decline in the FHR of at least 15 beats per minute and lasting 15 seconds, on the nonstress test and pregnancy outcome. Of the 505 nonstress tests, the results were considered either reactive (424 to 84%) or nonreactive (81 to 16%). Variable FHR decelerations or bradycardias were encountered on 95 nonstress tests (18.8%) in 80 (33.5%) postdate patients. Fetal heart rate bradycardia was encountered in nine patients (3.8%). Based on the last nonstress test, pregnancy outcome for the nonreactive group was less favorable than for the reactive group. However, when the reactive group was separated as to whether FHR decelerations or bradycardias were present or absent on the last test, the reactive group with FHR decelerations had a significant increase in meconium passage, cesarean delivery for fetal distress, and Apgar scores less than 7 at one minute. This group also had a similarly poor outcome as the nonreactive group of postdates patients. These data suggest that the nonstress test, when reactive without evidence of FHR decelerations, is a reliable indicator of fetal well-being in the postdate pregnancy. However, a reactive nonstress test with evidence of FHR decelerations is associated with a significant increase in perinatal morbidity.

Emergency hysterectomy for obstetric hemorrhage.

From 1978 to 1982, 70 cases of emergency hysterectomy for obstetric hemorrhage were performed at Los Angeles County/University of Southern California Women's Hospital. Sixty hysterectomies followed cesarean section, and ten were performed for hemorrhage after vaginal delivery. The most common indication for hysterectomy was atony (43%) followed by placenta accreta (30%), uterine rupture (13%), extension of a low transverse incision (10%), and leiomyomata preventing uterine closure and hemostasis (4%). Hysterectomies performed for atony had a significant association with the following factors when compared to hysterectomies performed for other indications: 1) amnionitis, 2) cesarean section for labor arrest, 3) oxytocin augmentation of labor, 4) MgSO4 infusion, and 5) fetal weight. Fifty-seven percent of hysterectomies performed for placenta accreta were associated with a previous cesarean section. During the study period, 53% of all patients presenting at term with both a placenta previa and one or more previous cesarean sections, subsequently underwent hysterectomy for placenta accreta. Even with a broad inclusion of risk factors, only 74% of patients developing a hemorrhagic complication leading to hysterectomy can be identified before delivery.

Neonatal nucleated red blood cell and lymphocyte counts in fetal brain injury.

OBJECTIVE: To determine whether neonatal lymphocyte or nucleated red blood cell (RBC) counts can be used to date fetal neurologic injury. METHODS: Singleton, term infants with hypoxic-ischemic encephalopathy, permanent neurologic impairment, and sufficient laboratory data were divided into two groups: infants with preadmission injury, manifested by a nonreactive fetal heart rate (FHR) pattern from admission until delivery; and infants with acute injury, manifested by a normal FHR pattern followed by a sudden prolonged FHR deceleration. Lymphocyte and nucleated RBC values were compared with published high normal counts for normal neonates: 8000 lymphocytes/mm3 and 2000 nucleated RBCs/mm3. RESULTS: The study population consisted of 101 neonates. In the first hours of life, lymphocyte counts were elevated among injured newborns, and then the counts rapidly normalized. Brain-injured neonates were 25 times more likely to have a lymphocyte count greater than 8000 than were normal neonates (54 [62%] of 87 versus 6 [7%] of 84; odds ratio 25.5; 95% confidence interval 8.8, 80.1; P < .001). The mean lymphocyte count tended to be higher in the preadmission-injury group than in the acute-injury group. In comparison, nucleated RBC values were not correlated as strongly with neonatal hours of life; nucleated RBC counts tended to be higher and persist longer among neonates with preadmission injury than among those with acute injury. CONCLUSION: Compared with normal levels, both lymphocyte and nucleated RBC counts were elevated among neonates with fetal asphyxial injury. Both counts appear to be more elevated and to remain elevated longer in newborns with preadmission injury than in infants with acute injury. However, the rapid normalization of lymphocyte counts in these injured neonates limits the clinical usefulness of these counts after the first several hours of life.

Twice a cesarean, always a cesarean?

The cesarean delivery rate has quadrupled during the past two decades, resulting in considerable attention focused on alternatives to cesarean birth. One option, vaginal birth after one previous cesarean, has come to be recognized as an acceptable alternative to routine elective repeat cesarean delivery. The purpose of this report was to evaluate whether women with two previous cesareans can safely undergo a trial of labor. Between July 1, 1982 and June 30, 1986, data were collected prospectively on all women with previous cesareans. Those with a known classical incision or a medical or obstetric contraindication to a trial of labor were excluded from an attempted vaginal delivery. During this period, 67,784 patients were delivered, of whom 6250 (9.2%) had had a previous cesarean. Of the 6250 previous-cesarean patients, 1088 (17.4%) had had two previous cesareans; of these, 501 (46%) underwent a trial of labor and 346 (69%) delivered vaginally. Whereas the overall rate of uterine dehiscence was 3%, the rate in those women who attempted a vaginal delivery was 1.8%, versus 4.6% in those who did not. Overall, oxytocin was used in 284 (57%) and was associated with a dehiscence rate of 2.1%, versus 1.4% in the no-oxytocin group. Successful vaginal delivery was related significantly to the use of oxytocin and to a previous vaginal delivery. Trial of labor in patients with two previous cesareans appears to be a reasonable consideration.

Hypogastric artery ligation for obstetric hemorrhage.

Ligation of the hypogastric arteries has been recommended for control of obstetric hemorrhage. However, specific information regarding its effectiveness is lacking. The hospital charts of 19 patients undergoing bilateral hypogastric artery ligation for the control of otherwise intractable obstetric hemorrhage were reviewed. Indications included uterine atony (15), lateral extension of a low-transverse uterine incision (three), and placenta accreta (one). This procedure was effective in controlling bleeding in eight of 19 patients (42%). Hysterectomy was necessary in the remaining 11 patients. In these patients, blood loss, operating time, and intraoperative morbidity was increased when compared with a group of 59 patients undergoing emergency hysterectomy for obstetric hemorrhage without prior ligation of the hypogastric arteries. Surgical approaches to hypogastric artery ligation are discussed.

A comparison of cardiac index in normal term pregnancy using thoracic electrical bio-impedance and oxygen extraction (Fick) techniques.

OBJECTIVE: To correlate cardiac index in normal late third-trimester pregnancy using the thoracic electrical bio-impedance technique with that obtained from the oxygen extraction technique. METHODS: Eight carefully screened normal pregnant women underwent assessment of cardiac index using both the thoracic electrical bio-impedance technique and the oxygen extraction technique. Measurements were obtained in various positions. RESULTS: The correlation was good between the thoracic electrical bio-impedance and oxygen extraction techniques in the left lateral (r = 0.915) and right lateral (r = 0.863) positions, and the intercepts at the midpoints of the oxygen extraction data in these positions suggested good absolute correlation as well. Correlation between thoracic electrical bio-impedance and the Fick cardiac index was poor in all other positions. CONCLUSIONS: Thoracic electrical bio-impedance cardiac index assessment is influenced by maternal position and must be used with caution in clinical research protocols. This technique appears to be inappropriate for general clinical use during pregnancy.

Update on external cephalic version performed at term.

External cephalic version under tocolysis at term was investigated during a prospective study at the Los Angeles County/University of Southern California Medical Center from October 1, 1979 to March 16, 1983. Two hundred twelve patients were considered for attempted version. Forty-one patients were excluded, and 23 patients as previously reported were randomized to the control group. The procedure was successful in 73% (108 of 148). Of the 102 successful versions observed until delivery (six lost to follow-up), 93% (95 of 102) presented in labor with a vertex presentation; seven fetuses reverted to abnormal lies. The cesarean section rate in the success group with a vertex presentation was 24% (23 of 95).