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.

The Effects of Evolution are Local: Evidence from Experimental Evolution in Drosophila.

One of the enduring temptations of evolutionary theory is the extrapolation from short-term to long-term, from a few species to all species. Unfortunately, the study of experimental evolution reveals that extrapolation from local to general patterns of evolution is not usually successful. The present article supports this conclusion using evidence from the experimental evolution of life-history in Drosophila. The following factors demonstrably undermine evolutionary correlations between functional characters: inbreeding, genotype-by-environment interaction, novel foci of selection, long-term selection, and alternative genetic backgrounds. The virtual certainty that at least one of these factors will arise during evolution shreds the prospects for global theories of the effects of adaptation. The effects of evolution apparently don't generalize, even though evolution is a global process.

Fetal heart rate observations in the brain-damaged infant.

The objective of this study was to describe the fetal heart rate patterns and underlying pathophysiologic changes in the brain-damaged fetus. Fetuses with brain damage from hypoxic ischemic encephalopathy do not manifest uniform fetal heart rate patterns. However, these fetuses do show distinct fetal heart rate patterns that permit categorization based on their admission heart rate, subsequent changes in their baseline rate; and neonatal findings. Based on the observations of infants brain damaged in utero because of hypoxic ischemic encephalopathy, the intrapartum fetal management will depend on the admission fetal heart rate pattern, and the subsequent changes in the baseline rate.

Neonatal platelet counts in fetal brain injury.

UNLABELLED: The objective of this study was to determine whether neonatal platelet counts can be used in fetal brain injury. The initial platelet counts, expressed as 1000 per mm3, of singleton term infants with and without permanent asphyxial brain injury were compared. Neonates with encephalopathy were divided into 3 groups: I--nonreactive fetal heart rate (FHR) pattern from admission until delivery; II--reactive FHR pattern on admission followed by nonreactivity, tachycardia, a loss of variability and repetitive FHR decelerations; and III--acute: reactive FHR pattern followed by a sudden prolonged FHR deceleration that lasted until delivery. The neonates and platelet counts for each group were as follows: CONTROL: 104 neonates, mean 281 +/- 56, range 154 to 411; I: 60, mean 185 +/- 80, range 28 to 365; II: 34, mean 251 +/- 66, range 100 to 375; and III: 35, mean 267 +/- 93, range 86 to 569. Platelet counts were significantly lower in neonates with encephalopathy (p <0.001). Group I differed statistically from both Groups II and III (p <0.001). These data suggest an association between the FHR pattern, fetal asphyxial brain injury, and the initial platelet count in singleton term neonates. Further investigation should be pursued to clarify the physiological processes leading to this result.

Acute fetal asphyxia and permanent brain injury: a retrospective analysis of current indicators.

OBJECTIVE: To determine whether a term neonate who has had sufficient intrapartum asphyxia to produce persistent brain injury will manifest the following four criteria: profound acidemia (arterial pH <7.00), an APGAR score < or =3 for 5 min or longer, seizures within 24 h of birth, and multiorgan system dysfunction. METHODS: Singleton, liveborn, neurologically impaired neonates > or =37 weeks gestation who lived at least 6 days and had sufficient documentation of current intrapartum asphyxia criteria were retrospectively analyzed. Of these infants, solely neonates with acute fetal asphyxia due to a sudden prolonged FHR deceleration that lasted until delivery from a catastrophic event, e.g., uterine rupture, cord prolapse, were included. Organ system dysfunction was defined by separate criteria for each organ system. Dysfunction in one or more was defined as multiorgan system dysfunction. RESULTS: Of the 292 eligible infants in the registry, 47 satisfied the entry criteria. In these 47 neonates, 10 (21%) satisfied all 4 criteria for intrapartum asphyxia. CONCLUSIONS: Our retrospective study suggests that currently used indicators to define permanent fetal brain injury are not valid.

Does the onset of neonatal seizures correlate with the timing of fetal neurologic injury?

The onset of seizures after birth has been considered evidence of an intrapartum asphyxial event. The present study was undertaken to determine whether the timing of neonatal seizures after birth correlated with the timing of a fetal asphyxial event. Thus, singleton term infants diagnosed with hypoxic ischemic encephalopathy and permanent brain injury had a mean birth to seizure onset interval of 9.8 +/- 17.7 (range 1-90) hours. When these infants were categorized according to their fetal heart rate (FHR) patterns, the acute group (normal FHR followed by a sudden prolonged FHR deceleration that continued until delivery) tended to have earlier seizures than infants did within the tachycardia group (normal FHR followed by tachycardia, repetitive decelerations, and diminished variability) and the preadmission group (persistent nonreactive FHR pattern intrapartum). These seizure intervals were as follows: acute, 6.6 +/- 18.0 (range 1-90) hours; tachycardia, 11.1 +/- 17.1 (range 1-61) hours; and preadmission, 11.8 +/- 17.9 (range 1-79) hours (p < 0.05). But the range varied widely and no group was categorically distinct. In conclusion, the onset of neonatal seizures after birth does not, in and of itself, appear to be a reliable indicator of the timing of fetal neurologic injury.

Ambulatory obstetrical care: strategies to reduce telephone liability.

The telephone will become the centerpiece of ambulatory care services. As such, a pertinent aspect of office procedures will necessarily include a protocol to manage and document telephone calls. Encourage your office staff to use good telephone manners, as listed in Table 5. The net result should be a reduction in telephone liability risks and an enhanced reputation for your office.

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.

The fetal admission test and intrapartum fetal death.

Our objective was to describe the admission and subsequent intrapartum fetal heart rate (FHR) patterns in 21 singleton term pregnancies with an intrapartum fetal death. Through a retrospective chart review, 21 pregnancies with a term intrapartum fetal death were divided into 2 groups based on the fetal admission test (FAT): Group I-reactive (one or more FHR accelerations of 15 bpm x 15 sec in the first 30 min of monitoring); and Group II-nonreactive (NR [the absence of accelerations]). The FAT was compared with the subsequent intrapartum FHR pattern. Of the 21 deaths, the FAT was reactive in 7 fetuses (33%) or NR in 14 fetuses (67%). While the demographic features of these groups were statistically similar, Group II had higher rates of meconium (12 out of 14 (86%) vs. 2 out of 7 [29%] p = 0.017) and admission FHR decelerations (9 out of 14 (64%) vs. 1 out of 7 [14%] p = 0.06). In Group I, a sudden catastrophic event such as a uterine rupture produced a prolonged FHR deceleration in six fetuses (86%). One (14%) fetus died after a Hon pattern. In Group II, four patients had a stair steps to death pattern. Intrapartum fetal death can occur after a reactive or NR FAT. With a reactive FAT, a catastrophic event appears necessary to cause fetal death. The higher rates of meconium, FHR decelerations, and stair steps to death patterns in the NR group suggest the underlying basis for the fetal demise was related to preadmission fetal compromise.

Permanent Erb's palsy: a lack of a relationship with obstetrical risk factors.

Our objective was to investigate the association between permanent Erb's palsy and the presence of historic obstetrical risk factors. Cases of documented permanent Erb's palsy from our national registry of children with Erb's palsy were extracted and analyzed for the purpose of this descriptive study. Maternal and neonatal records were reviewed for demographic data, prenatal care, labor characteristics, delivery outcome, and long-term follow-up. Sixty-three infants with permanent Erb's palsy were identified. Seventeen (27.0%) mothers were nulliparous. Mean +/- SD (range) gestational age at delivery and birthweight were 39.9 weeks +/- 1.3 (37-43) and 4501 g +/- 625 (3352-6905), respectively. Maternal and perinatal characteristics of these cases were (n [%]): nondiabetic-56 (89%); weight gain <40 lb-48 (76%); normal labor-57 (91%); 2nd stage <2.0 hr-54 (86%); midpelvic procedure-13 (21%); and shoulder dystocia-59 (94%). There were no statistically significant differences between patients with birthweight >4500 g (n = 26 [41%]) and those with birthweight < or =4500 g (n = 37 [59%]). These data suggest that historic risk factors for neonatal brachial plexus injury may not be associated with permanent Erb's palsy.

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.

Intrapartum fetal asphyxial brain injury with absent multiorgan system dysfunction.

Current understanding of the physiologic mechanisms of intrapartum fetal asphyxial brain injury has suggested a strong association with multiorgan system injury. Thus the purpose here is to describe 14 cases of severe fetal brain injury with absent multiorgan system dysfunction (MSD). The study population was drawn from a national registry for brain injured infants. MSD was defined by clinical criteria demonstrated to reflect asphyxial injury to the pulmonary, renal, cardiac, hematologic, hepatic, and gastrointestinal systems. Involvement of one other organ in addition to the brain was defined as multiorgan system dysfunction. All infants were diagnosed with hypoxic-ischemic encephalopathy (HIE) in the neonatal period and went on to have permanent central nervous system (CNS) injury and MSD criteria were not met. Of the 292 term, singleton infants with HIE and permanent neurologic injury, 57 (20%) satisfied the entry criteria; of these, 14 (36%) had no MSD. The underlying basis for the fetal brain injury were: uterine rupture, 6 (43%), prolonged FHR deceleration, 5 (36%), fetal exsanguination, 1 (7%), cord prolapse, 1 (7%), and maternal cardiopulmonary arrest, 1 (7%). The mean duration of the prolonged FHR deceleration was 32.1 +/- 9.1 (range 19-51) minutes. All infants were later diagnosed with cerebral palsy. Intrapartum fetal asphyxial brain injury may not necessarily proceed through a physiologic mechanism in which the fetal circulation is centralized and endorgans damaged. These acute injuries, associated with a prolonged FHR deceleration, may be linked to severely decreased cardiac output and hypotension that cause vulnerable portions of the brain to be injured before other organs.

Catastrophic shoulder dystocia and emergency symphysiotomy.

We present three cases of shoulder dystocia unrelieved by standard maneuvers, including cephalic replacement. Symphysiotomy was performed in an effort to preserve fetal life. All three infants sustained severe neurologic injury and later died. Maternal morbidity including urinary incontinence was significant but responded to treatment. Symphysiotomy may be the only method of relieving some cases of shoulder dystocia, but its role remains unclear because of operator inexperience and maternal morbidity.

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.