Eveline H. Shue

Single versus multiple probe blocks of P300-based concealed information tests for self-referring versus incidentally obtained information

UNLABELLED The aim of the present study was to compare two protocols and two information types on detection of concealed knowledge. Four independent groups of subjects were run. Two were tested on probe stimuli of a self-referring (AUTO) nature and two were tested on incidentally acquired details of a mock crime (MOCK). Each pair of groups was run either in a one-probe (1PB) or multiple probe (6PB) block. In the single probe block, which was repeated three times with a different probe on each block, one probe item was randomly repeated multiple times in a Bernoulli series with frequently presented, meaningless or irrelevant items. There was also a rare target item designed to force attention to the stimulus screen. All stimulus types were of the same category within each block. In contrast, in the multiple probe (and category) block, rare probes, rare targets and frequent irrelevant items were repeatedly presented in a Bernoulli series within one block. MAJOR RESULTS There was a difference in task demand as measured by reaction time between the two protocols (the multiple probe protocol was more demanding), and a difference trend in P300 detection sensitivity between protocols for both information types combined in favor of the 1PB (p<.07). With both protocols combined, there was a trend (p<.07) favoring detection of familiar versus incidentally learned information. In terms of P300 amplitudes, both protocols showed the usual result that P300 to probes was greater than that to irrelevants. Also, as with detection rates, self-referring information was better detected in terms of Probe-Irrelevant P300 amplitude differences than mock crime information, regardless of protocol. There was no effect of time passage across the repeated blocks of the one-probe protocol. Methodological problems with the multiple probe protocol as utilized in most recent publications are discussed.

Plasmalemmal Vesicle Associated Protein-1 (PV-1) is a marker of blood-brain barrier disruption in rodent models

BackgroundPlasmalemmal vesicle associated protein-1 (PV-1) is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS) diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state.ResultsWe demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated.ConclusionOur results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.

Plasmalemmal Vesicle Associated Protein-1 Is a Novel Marker Implicated in Brain Tumor Angiogenesis

Purpose:Plasmalemmal vesicle associated protein-1 (PV-1) is up-regulated in the endothelium of human glioblastoma. We sought to further characterize the expression pattern of PV-1 in human brain tumors and interrogate its role in brain tumor angiogenesis. Experimental Design: Quantitative reverse transcription-PCR and in situ hybridization were used to measure PV-1 expression in a panel of 46 human brain tumors and related pathologic states. Matrigel tubulogenesis assays and cell migration assays were used to show function of PV-1 in primary human endothelial cells (HMVEC) under gene knockdown conditions. Results:PV-1 is selectively up-regulated in a variety of high-grade human brain tumors, including glioblastoma and metastatic carcinoma, as well as other cerebral disorders associated with blood-brain barrier disruption, such as acute ischemia. Expression levels were reduced in low-grade neoplasia; however, tumors associated with the ependyma and choroid plexus, known sites of PV-1 expression, also exhibited robust expression. Cerebral expression of PV-1 mRNA was confined to endothelial cells in all cases. PV-1 expression was induced in HMVEC cells in vitro by exposure to medium conditioned by U87MG and U251MG human brain tumor cell lines and by medium supplemented with exogenous vascular endothelial growth factor or scatter factor/hepatocyte growth factor. RNA interference–mediated inhibition of PV-1 induction in HMVEC cells blocked Matrigel-induced tubulogenesis and inhibited cell migration induced by conditioned medium or angiogenic growth factors. Conclusions: Our results confirm that PV-1 is preferentially induced in the endothelium of high-grade human brain tumors. Inhibition of PV-1 expression is associated with failure of endothelial differentiation in vitro. PV-1 represents a novel marker of brain tumor angiogenesis and integrity of the blood-brain barrier and is a potential therapeutic target.

Predictors of poor prognosis in prenatally diagnosed sacrococcygeal teratoma: A multiinstitutional review

INTRODUCTION Attempts at defining predictors of poor outcome in fetal sacrococcygeal teratoma (SCT) have been hampered by small patient numbers. We sought to validate the utility of tumor volume to fetal weight ratio (TFR) as a predictor of poor prognosis and to identify other morphological outcome predictors in a multicenter series. METHODS Records of prenatally diagnosed SCT at three fetal centers from 1986 to 2011 were reviewed. Prenatal imaging characteristics including TFR, morphology, hydrops, and placentomegaly were assessed. Poor prognosis was defined as fetal demise, need for fetal intervention, or perinatal death. Receiver operating characteristic (ROC) analysis was used to select a TFR cutoff value. RESULTS Seventy-nine fetuses with SCT were evaluated. Eleven pregnancies ending in elective termination were excluded. ROC analysis revealed that TFR >0.12 prior to 24 weeks gestation was predictive of poor prognosis (AUC=0.913; Sensitivity=91.7%, Specificity=76.2%, PPV=86.8%; NPV=84.2%). Solid tumor morphology and presence of hydrops were found to be predictors of poor prognosis. None of the factors associated with poor prognosis were independent predictors on multivariate analysis. CONCLUSION This study validates TFR >0.12 prior to 24 weeks gestation as an objective predictor of outcomes in fetuses with SCT that can be easily applied in most clinical settings.

Tumor metrics and morphology predict poor prognosis in prenatally diagnosed sacrococcygeal teratoma: A 25-year experience at a single institution

PURPOSE Some fetuses with sacrococcygeal teratoma (SCT) develop hydrops, but there is no consensus on an appropriate prognostic marker for poor prognosis. The purpose of this study is to establish predictors of poor prognosis in fetuses with SCT. METHODS A retrospective review of patients with prenatally diagnosed SCT from 1986 to 2011 was performed. Patients with outcome data and ultrasound exams before 32 weeks gestational age (GA) were included (n=37). Tumor volume-to-fetal weight ratio (TFR) and tumor morphology were assessed as sonographic predictors of poor prognosis. RESULTS Twelve patients (32%) had good prognosis, and twenty-five patients (68%) had poor prognosis. All patients with poor prognosis had a morphology score ≥ 3, which is a significant predictor of poor prognosis (p <0.0001). TFR was assessed, and a receiver operating characteristic (ROC) analysis identified a cutoff value of 0.12 before 24 weeks GA and 0.11 before 32 weeks GA as predictors for poor prognosis. TFR is a significant predictor of poor prognosis (p<0.0001). CONCLUSIONS Patients with cystic SCT all had good prognosis. TFR >0.12 was validated as a sonographic predictor of poor prognosis. TFR and tumor morphology can be used to counsel expectant families with prenatally diagnosed SCT regarding prognosis.

Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia

PURPOSE Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. METHODS CDH was created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. RESULTS Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82%±12% in Normal-Placebo, 61%±5% in CDH-Placebo, 116%±6% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105%±15% in Normal-Placebo, 82%±3% in CDH-Placebo, 158%±16% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p=0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p=0.0002). CONCLUSIONS PDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH.

Advances in Prenatal Diagnosis and Treatment of Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) is a common birth anomaly. Absence or presence of liver herniation and determination of lung-to-head ratio are the most accurate predictors of prognosis for fetuses with CDH. Though open fetal CDH repair has been abandoned, fetal endoscopic balloon tracheal occlusion promotes lung growth in fetuses with severe CDH. Although significant improvements in lung function have not yet been shown in humans, reversible or dynamic tracheal occlusion is promising for select fetuses with severe CDH. This article reviews advances in prenatal diagnosis of CDH, the experimental basis for tracheal occlusion, and its translation into human clinical trials.

An isolated Merkel cell carcinoma metastasis at a distant cutaneous site presenting as a second 'primary' tumor.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Disease progression usually occurs via lymphatic spread to regional lymphatic draining basins, followed by distant metastasis. We report the clinical course, histopathology and genetic analysis of a 69‐year‐old woman with likely hematogenous spread of cutaneous neuroendocrine carcinoma manifesting as a single metastatic lesion to a distant cutaneous site. Although the possibility of two cutaneous primary MCCs was considered, array comparative genomic hybridization (aCGH) identified identical distal amplification of a region of chromosome 12p, and synchronous loss of chromosomes 8p and 17p, effectively ruling out the possibility of independent primaries. We propose that this represents a primary cheek MCC with rapid, isolated cutaneous metastasis to the contralateral ankle via hematogenous spread. The distinction between a second primary MCC and a distant cutaneous metastasis clearly has important implications with regard to staging, treatment and prognosis. To our knowledge, this represents the first report of the use of aCGH to clarify the relationship of multiple synchronous cutaneous MCCs and the first report of a single distant cutaneous focus of hematogenous spread. Our data calls into question prior reports alleging multiple cutaneous primaries of this very rare tumor.

Aberrant pulmonary lymphatic development in the nitrofen mouse model of congenital diaphragmatic hernia

PURPOSE Many infants develop a postsurgical chylothorax after diaphragmatic hernia repair. The pathogenesis remains elusive but may be owing to dysfunctional lymphatic development. This study characterizes pulmonary lymphatic development in the nitrofen mouse model of CDH. METHODS CD1 pregnant mice were fed nitrofen/bisdiamine (N/B) or olive oil at E8.5. At E14.5 and E15.5, lung buds were categorized by phenotype: normal, N/B without CDH (N/B - CDH), or N/B with CDH (N/B+CDH). Anti-CD31 was used to localize all endothelial cells, while anti-LYVE-1 was used to identify lymphatic endothelial cells in lung buds using immunofluorescence. Differential protein expression of lymphatic-specific markers was analyzed. RESULTS Lymphatic endothelial cells localized to the mesenchyme surrounding the airway epithelium at E15.5. CD31 and LYVE-1 colocalization identified lymphatic endothelial cells. LYVE-1 expression was upregulated in N/B+CDH lung buds in comparison to N/B - CDH and normal lung buds by immunofluorescence. Western blotting shows that VEGF-D, LYVE-1, Prox-1, and VEGFR-3 expression was upregulated in N/B+CDH lung buds in comparison to N/B - CDH or control lung buds at E14.5. CONCLUSIONS Lung lymphatics are hyperplastic in N/B+CDH. Upregulation of lymphatic-specific genes suggests that lymphatic hyperplasia plays an important role in dysfunctional lung lymphatic development in the nitrofen mouse model of CDH.

Implantable Ultralow Pulmonary Pressure Monitoring System for Fetal Surgery

Congenital pulmonary hypoplasia is a devastating condition affecting fetal and newborn pulmonary physiology, resulting in great morbidity and mortality. The fetal lung develops in a fluid-filled environment. In this paper, we describe a novel, implantable pressure sensing and recording device which we use to study the pressures present in the fetal pulmonary tree throughout gestation. The system achieves 0.18 cm H 2O resolution and can record for 21 days continuously at 256 Hz. Sample tracings of in vivo fetal lamb recordings are shown.