Behavioral, Histopathologic, and Molecular Biological Responses of Nanoparticle- and Solution-Based Formulations of Vincristine in Mice.

Clinical use of the chemotherapeutic agent vincristine (VCR) is limited by chemotherapy-induced peripheral neuropathy (CiPN). A new formulation of VCR encapsulated by nanoparticles has been proposed and developed to alleviate CiPN. We hypothesized in nonclinical animals that the nanoparticle drug would be less neurotoxic due to different absorption and distribution properties to the peripheral nerve from the unencapsulated free drug. Here, we assessed whether VCR encapsulation in nanoparticles alleviates CiPN using behavioral gait analysis (CatWalk), histopathologic and molecular biological (RT-qPCR) approaches. Adult male C57BL/6 mice were assigned to 3 groups (empty nanoparticle, nano-VCR, solution-based VCR, each n = 8). After 15 days of dosing, animals were euthanized for tissue collection. It was shown that intraperitoneal administration of nano-VCR (0.15 mg/kg, every other day) and the empty nanoparticle resulted in no changes in gait parameters; whereas, injection of solution-based VCR resulted in decreased run speed and increased step cycle and stance (P < 0.05). There were no differences in incidence and severity of degeneration in the sciatic nerves between the nano-VCR-dosed and solution-based VCR-dosed animals. Likewise, decreased levels of a nervous tissue-enriched microRNA-183 in circulating blood did not show a significant difference between the nano- and solution-based VCR groups (P > 0.05). Empty nanoparticle administration did not cause any behavioral, microRNA, or structural changes. In conclusion, this study suggests that the nano-VCR formulation may alleviate behavioral changes in CiPN, but it does not improve the structural changes of CiPN in peripheral nerve. Nanoparticle properties may need to be optimized to improve biological observations.

Cerebral hemodynamic response to short-term maternal hyperoxygenation in fetuses with borderline small left hearts.

BACKGROUND: Hypoxia delays brain maturation and contributes to neurodevelopmental morbidity in fetuses with congenital heart defects (CHDs). Maternal hyperoxygenation (MH) can, in theory, promote oxygen/nutrient delivery to the fetal brain, owing to an improved heart structure/function and increased fetal oxygen content. We aimed to determine whether MH alters fetal cerebral hemodynamics in fetuses with CHD. METHODS: Twenty-eight fetuses with borderline small left hearts and 28 age-matched normal fetuses were enrolled and subdivided by gestational age (GA): 23+ 0 ~ 27+ 6 weeks and 28+ 0 ~ 36+ 6 weeks. The middle cerebral artery pulsatility index (MCA-PI), vascular index (VI), flow index (FI) and vascular/flow index (VFI) were measured with baseline room air, after 10 min of MH and after 10 min of recovery for all subjects. RESULTS: MCA-PI, VI, FI and VFI did not differ with MH in the normal fetuses. In fetuses with borderline small left hearts, MCA-PI increased and VI, FI and VFI significantly decreased during the 3rd trimester (from 1.44 ± 0.27, 3.19 ± 0.87, 56.91 ± 9.19, and 1.30 ± 0.33 at baseline to 1.62 ± 0.15, 2.37 ± 0.37, 45.73 ± 4.59, and 0.94 ± 0.15 during MH, respectively, P < 0.05), but this response was not apparent during mid-gestation (p > 0.05). These parameters returned to the baseline levels during the recovery phase. The change in cerebral perfusion depended on the baseline MCA-PI and increased the combined cardiac index (CCOi). CONCLUSIONS: MH alters the cerebral hemodynamics of fetuses with borderline small left hearts during the third trimester. Further investigation is needed to determine whether MH may benefit brain growth and neurodevelopment in this high-risk population.

Fetal pulmonary atresia with ventricular septal defect: Features, associations, and outcome in fetuses with different pulmonary circulation supply types.

OBJECTIVES: To assess features and outcome in fetuses with pulmonary atresia with ventricular septal defect (PA-VSD). METHODS: Fetuses with PA-VSD were prospectively enrolled and grouped on the basis of the pulmonary blood supply, including type A (only arterial duct [DA]), type B (both DA and major aortopulmonary collateral arteries [MAPCAs] present), and type C (MAPCAs only). The echocardiography features, associated chromosomal/genetic malformations, and postnatal outcome were compared among the three groups. RESULTS: Fifty-five fetuses with PA-VSD were enrolled. The presence of confluent PAs varied, with the highest displaying rate in type A and lowest rate in type C (100% vs 41.1%). The intrapericardial pulmonary arteries in all groups were hypoplastic but smaller in types B and C than in type A (P < .05). Deletion of 22q11.2 and right aortic arch were more frequently observed in types B and C than in type A. At the end of the study, overall survival rates in type C were lower than those in type A (22.1% vs 77.3%). CONCLUSION: There are great differences in the size of pulmonary arteries, associated genetic malformations, and perinatal outcomes among fetuses with PA-VSD. These results could be used for family counseling and surgical planning.

Mummified Thyroid Nodules: Conventional and Contrast-Enhanced Ultrasound Features.

OBJECTIVES: The purpose of our study was to highlight the conventional and contrast-enhanced ultrasound (US) features of mummified thyroid nodules, which should help differentiate them from histologically proven papillary thyroid carcinomas (PTCs). METHODS: Thirty-one patients with 33 mummified thyroid nodules, which showed suspicious US findings that were suggestive of malignancy, as well as 33 patients with 38 surgically confirmed PTCs were enrolled in this study. We evaluated the size, shape, margin, echogenicity, presence of shadowing and halo, presence of punctate echogenic foci, vascularity, and contrast enhancement parameters for each nodule. The final diagnosis of mummified thyroid nodules was confirmed via fine-needle aspiration (FNA) or surgery. RESULTS: Of the 33 mummified thyroid nodules, 9 (27.3%) were confirmed by surgery to be benign, and 24 (72.7%) were proven by FNA to be benign. A univariate analysis indicated that the mummified thyroid nodules more frequently showed wider-than-tall shapes, marked hypoechogenicity, the presence of posterior shadowing, the absence of nodular vascularity, hypoenhancement or no enhancement, and peak index and area under the curve indices of less than 1 in the findings of preoperative US and contrast-enhanced US compared to PTCs. A multivariate analysis showed that marked hypoechogenicity and an area under the curve index of less than 1 were independent characteristics related to mummified nodules for discriminating from PTCs (all P < .05). CONCLUSIONS: Benign thyroid nodules may display shrinkage over time and may reveal malignant US features. Awareness of these findings and their connection with initial and follow-up US examinations should help identify mummified thyroid nodules and to avoid surgical excision or unnecessary FNA.

Velocity vector imaging echocardiography and NT-proBNP study of fetal cardiac function in pregnancy-induced maternal hypertension.

PURPOSE: To investigate whether acute and transient pressure overload in patients with pregnancy-induced hypertension affects cardiac function in fetuses. METHODS: We enrolled 104 singleton pregnant women with gestational ages ranging 30 to 33 weeks, visiting for prenatal care. Among them, 34 had gestational hypertension (GH), 32 had preeclampsia (PE), and 38 were healthy and formed the control group. Conventional echocardiographic and velocity vector imaging (VVI) variables were prospectively collected. Blood levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured from cord blood drawn at birth. RESULTS: The fetuses of mothers with preeclampsia had significantly lower left (LV) and right ventricle (RV) diastolic strain rate (SRd) and RV strain (S) and systolic strain rate (SRs) than controls. LV and RV S, SRd, and SRS were not different in fetuses of mothers with GH and controls. The NT-proBNP levels were higher in fetuses of patients with PE than in GH and controls. CONCLUSIONS: In the third trimester of pregnancy, fetal biventricular function and NT-proBNP levels are not significantly influenced by GH. Fetuses of mothers with PE present signs of LV and RV diastolic dysfunction, right ventricular systolic dysfunction, and elevated NT-pro-BNP levels. VVI echocardiography appears more sensitive than conventional echocardiography to evaluate fetal cardiac function.

Left ventricular function of patients with pregnancy-induced hypertension evaluated using velocity vector imaging echocardiography and N-terminal pro-brain natriuretic peptide.

PURPOSE: To investigate whether acute and transient pressure overload in patients with pregnancy-induced hypertension (PIH) affects left ventricular (LV) systolic function. METHODS: From pregnancy to 3 months after delivery, 82 patients were analyzed: 27, 25, and 30 with gestational hypertension, preeclampsia, and the healthy control group, respectively. Conventional echocardiography and velocity vector imaging (VVI) were performed, and blood levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) were analyzed. RESULTS: Compared with the control group, patients with gestational hypertension had significantly lower mean LV peak global longitudinal strain. Importantly, during both pregnancy and after delivery, patients with preeclampsia had significantly lower global longitudinal, circumferential, and radial strain compared with the control group. The NT-pro-BNP levels were significantly higher in patients with PIH compared with normotensive pregnancies, and this situation continued for 3 months after delivery in women with preeclampsia. CONCLUSIONS: In pregnancies complicated by pregnancy-induced hypertension, especially preeclampsia, the systolic function is impaired and NT-pro-BNP levels are elevated compared with normal pregnancy. Velocity vector imaging (VVI) is more sensitive than left ventricular ejection fraction to evaluate heart function in patients with PIH.

Analysis of left ventricular fluid dynamics in dilated cardiomyopathy by echocardiographic particle image velocimetry.

OBJECTIVE: The aim was to analyze left ventricular (LV) fluid dynamics in dilated cardiomyopathy (DCM) by using echocardiographic particle image velocimetry (E-PIV). METHODS: Twenty patients with DCM and twenty healthy volunteers were examined. LV ultrasound contrast was administered by intravenous bolus injection. At least three dynamic contrast-enhanced echocardiographic images of cardiac cycles from apical three-chamber view and four-chamber view were obtained. The acquired echocardiographic image loops were processed off line by HyperFlow. RESULTS: In healthy hearts, the filling flow in the left ventricle finally comes to be a single large clockwise vortex, which smoothly redirects the blood to the outflow tract. Meanwhile, aberrant flow patterns are observed in the patients with DCM. In the DCM group, the vortex area (0.237 ± 0.063 vs 0.196 ± 0.129, P = .029), vortex depth (0.396 ± 0.134 vs 0.293 ± 0.143, P = .025), and vortex length (0.534 ± 0.089 vs 0.435 ± 0.176, P = .004) are significantly higher. The flow force angle (29.979 ± 8.208 vs 35.896 ± 6.044, P = .013) is significantly lower, and energy dissipation (0.975 ± 0.552 vs 0.578 ± 0.295, P = .006) is significantly higher. A negative linear relation is indicated between the following pairs of parameters: vortex depth and LV ejection fraction (EF) (r = -.350, P = .027); vortex length and LV EF (r = -.321, P = .044); energy dissipation and LV EF (r = -.523, P = .001). A positive linear relation is indicated between flow force angle and LV EF (r = .365, P = .021). CONCLUSION: E-PIV can effectively and quantitatively evaluate LV fluid dynamics in patients with DCM. LV fluid dynamics and LV systolic function interact with and affect each other.

Contrast-enhanced ultrasound of small cell carcinoma in urinary bladder: a case report and review of literature.

BACKGROUND: Small cell carcinoma of the urinary bladder (SCCB) is a relatively rare malignant bladder tumor, and few reports have investigated the microvasculature of SCCB imaged using contrast-enhanced ultrasound (CEUS). CASE PRESENTATION: A 63-year-old female was admitted to our hospital after experiencing painless gross hematuria for one week. The gray-scale ultrasound (US) demonstrated a 4.8 × 3.4 × 3.6-cm3 hypoechoic mass in the apex of the urinary bladder with a wide base and an irregular surface; the mass did not move with changes in body position. Color Doppler flow imaging (CDFI) showed rich blood flow in the mass. CEUS with low mechanical index (MI) of 0.06 confirmed a highly enhanced 5.0 × 3.3 × 3.8 cm3 mass within the bladder at the apex wall. The time-intensity curves (TICs) showed a wash-in time of 10 s, a time to peak (TTP) of 33 s, a signal intensity (SI) of 62.7% and a wash-out time > 60 s. Finally, the transurethral resection of the bladder tumor (TURBT) was performed, and the pathological examination proved the diagnosis of SCCB. CONCLUSION: CEUS can provide valuable information related to the rich microvasculature of SCCB, which may be helpful in its diagnosis.

Reduced fetal brain fissures depth in fetuses with congenital heart diseases.

OBJECTIVE: To screen and detect cortex gyration in fetuses with congenital heart disease (CHD) using Ultrasonography (US) during routine obstetric scans. METHODS: The depth of the Sylvian fissure (SF), parieto-occipital fissure (POF), and calcarine (CF) fissure were prospectively serially measured and compared in 45 fetuses with CHD and 45 normal fetuses. Cardiac hemodynamic parameters, including aortic valve diameter (AV), pulmonary valve diameter (PV), velocity time integral of the aortic valve (VTIav), and velocity time integral of the pulmonary valve (VTIpv), were recorded. Correlations between the fissure depths and the prenatal cardiac hemodynamic parameters and postnatal neurodevelopmental scores were assessed. RESULTS: SF, POF, and CF were decreased in CHD fetuses compared with the controls in late of pregnancy (P < 0.01). The diagnostic category was independently associated with smaller fissure depths in fetuses with CHD (adjusted R2 = 0.472 for SF, 0.465 for POF, and 0.425 for CF). Correlations were observed between small fissure depths and decreased left heart hemodynamic parameters (AV and VTIav) in fetuses with CHD. The SF depth was positively correlated with the neurodevelopmental scores (P < 0.01). CONCLUSIONS: US can be used to screen for abnormal fetal brain cortex development during routine obstetric scans and to evaluate the maturation progress during close follow-up. © 2016 John Wiley & Sons, Ltd.

Evaluation of right ventricular function in fetal hypoplastic left heart syndrome using spatio-temporal image correlation (STIC).

BACKGROUND: Postnatal outcome of fetuses with hypoplastic left heart syndrome (HLHS) is mainly determined by right ventricular function. In the present study we used spatio-temporal image correlation (STIC) to assess right ventricular function of fetuses with HLHS. METHODS: Three-dimensional ultrasound with STIC technique was used to acquire heart images from fetuses that had HLHS and the normal controls, between 24(+0) and 37(+6) weeks of gestation. Right ventricular end-diastolic volume (RVEDV) and right ventricular end-systolic volume (RVESV) were determined using the virtual organ computer-aided analysis software, and the parameters of right ventricular function were calculated. RESULTS: Both RVEDV and RVESV were found to be significantly higher in fetuses with HLHS as compared to that in normal controls (P < 0.001). There were no significant differences in the parameters between fetuses with and without a visible left ventricular cavity (P > 0.05). Compared to fetuses with HLHS plus mild tricuspid regurgitation (TR), fetuses with HLHS plus severe TR exhibited lower right ventricular stroke volume (RVSV), right ventricular cardiac output (RVCO) and standardized RVCO (P < 0.05). The right ventricular ejection fraction (RVEF) was significantly lower in HLHS fetuses that had severe TR (P < 0.001). CONCLUSION: As the right ventricle is solely responsible for maintenance of circulation, the right ventricular systolic function undergoes compensatory enhancement in fetuses with HLHS and mild TR, compared to that in normal controls. Size of the left ventricle does not significantly affect the right ventricular function in HLHS. However, right ventricular systolic function may be impaired prenatally in HLHS fetuses that have severe TR.

Increased hepatic stiffness as consequence of high hepatic afterload in the Fontan circulation: a vascular Doppler and elastography study.

UNLABELLED: Hepatic dysfunction is a recognized complication after Fontan palliation of congenital heart disease. We sought to quantitatively measure hepatic stiffness and vascular Doppler indices using ultrasound (US) and shear wave elastography (SWE) in a Fontan cohort. Subjects were prospectively recruited for echocardiography and real-time hepatic duplex US with SWE for hepatic stiffness (kPa). Doppler peak velocities, velocity time integral, resistive, pulsatility, acceleration indices (RI, PI, AI), and flow volume were measured in celiac artery, superior mesenteric artery, and main portal vein (MPV). A subset underwent cardiac catheterizations with liver biopsy. Correlations were explored between SWE, duplex, hemodynamic, and histopathologic data. In all, 106 subjects were studied including 41 patients with Fontan physiology (age 13.8 ± 6 years, weight 45.4 ± 23 kg) and 65 controls (age 15.0 ± 8.4 years, weight 47.9 ± 22 kg). Patients with Fontan physiology had significantly higher hepatic stiffness (15.6 versus 5.5 kPa, P < 0.0001), higher celiac RI (0.78 versus 0.73, P = 0.04) superior mesenteric artery RI (0.89 versus 0.84, P = 0.005), and celiac PI (1.87 versus 1.6, P = 0.034); while MPV flow volume (287 versus 420 mL/min in controls, P = 0.007) and SMA AI (829 versus 1100, P = 0.002) were lower. Significant correlation was seen for stiffness with ventricular end-diastolic pressure (P = 0.001) and pulmonary artery wedge pressure (P = 0.009). Greater stiffness correlated with greater degrees of histopathologic fibrosis. No significant change was seen in stiffness or other duplex indices with age, gender, time since Fontan, or ventricular morphology. CONCLUSION: Elevated hepatic afterload in Fontan, manifested by high ventricular end-diastolic pressures and pulmonary arterial wedge pressures, is associated with remarkably increased hepatic stiffness, abnormal vascular flow patterns, and fibrotic histologic changes. The MPV is dilated and carries decreased flow volume, while the celiac and superior mesenteric arterial RI is increased. SWE is feasible in this population and shows promise as a means for predicting disease severity on liver biopsy.

Z-score reference ranges for normal fetal heart sizes throughout pregnancy derived from fetal echocardiography.

OBJECTIVE: To construct Z-score reference ranges for normal fetal heart sizes throughout pregnancy. METHODS: This is a prospective cross-sectional investigation of 809 normal singleton fetuses from 11th week to term. Fetal transverse heart diameter (HD), heart length (HL), heart circumference (HC) and heart area (HA) were derived from two-dimensional echocardiography. The regression analyses of the mean (M) and the standard deviation (SD) for each parameter were calculated separately, using fetal somatic sizes as independent variables. A group of fetal heart diseases was assessed using these parameters. RESULTS: Strong correlations were found between fetal heart sizes and somatic sizes. Linear-cubic regression equations were each fitted to the models of the means of the heart sizes, whereas linear-quadratic equations were fitted to the models of the SDs. HD was the dependent variable that provided the highest correlation coefficient with all of the fetal sizes, followed by HL, HC and HA. All fetuses with Ebstein's anomaly and most with homozygous α-thalassemia-1 demonstrated Z-scores reflective of increased heart sizes. CONCLUSION: The calculation of Z-scores for heart sizes as a function of fetal somatic size is simple and may be useful for quantitative assessment of some cardiac diseases, particularly cardiomegaly caused by homozygous α-thalassemia-1.

[Assessment of the right ventricle function of fetus by spatio-temporal image correlation].

OBJECTIVE: To evaluate the superiority, feasibility and clinical signifi cance of the four-dimensional spatio-temporal image correlation (STIC) in detection of the right ventricle function of fetus. METHODS: Th e STIC dynamic images of 180 normal fetal hearts at 24+0 to 37+6 weeks of gestation were obtained by the three-dimensional (3D) probe. Th e post-process evaluation was done off -line with the virtual organ computer-aided analysis (VOCAL) software. The computer recorded the right ventricular end-diastolic volume (RVEDV), right ventricular end-systolic volume (RVESV), and then calculated the right stroke volume (RSV), the right cardiac output (RCO) and the right ejection fraction (REF). RCO was standardized by biometric measurements obtained at prenatal screening, including head circumference (HC), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW). RESULTS: The overall successful rate in image acquisition was 83.89% and the repeatability was favorable. After the standardization of fetal biometric parameters (HC, AC, FL) and the right ventricle function indexes (RVEDV, RVESV, RSV), RCO was increased with the gestational age while the REF and RCO/EFW fluctuated within a certain range. CONCLUSION: STIC technique can accurately and objectively measure the fetal ventricular volume and it might be a potential strategy in the clinical assessment of the fetal cardiac function.

Echocardiographic follow-up and pregnancy outcome of fetuses with cardiac asymmetry at 18-22 weeks of gestation.

OBJECTIVE: The goal of our study was to evaluate the evolution of cardiac findings and assess the pregnancy outcome of fetuses with cardiac asymmetry at midgestation. METHODS: We reviewed all fetuses with cardiac asymmetry at echocardiograms performed at 18-22 weeks of gestation from 2006 to 2013. The data collected included the gestational age at diagnosis, serial echocardiographic findings, karyotype testing, and pregnancy outcome. Excluded were cases of classical hypoplastic left heart syndrome (HLHS) at initial echocardiogram (i.e., aortic (AO) and/or mitral atresia or dysplasia with normal intracardiac connections), heterotaxy syndrome, twin pregnancy, fetal growth restriction, and coarctation of the aorta. RESULTS: Our study included 278 fetuses with cardiac asymmetry (defined as Z-scores of left ventricle length or diameter of less than -2). A total of 202 (72%) fetuses had normal variations in cardiac growth by prenatal and neonatal echocardiography, 69 (25%) fetuses were confirmed to have HLHS variant by autopsy or neonatal echocardiography (with an overall survival of 4.3%), and seven (3%) fetuses were terminated before 24 weeks of gestation because of abnormal karyotypes. None of the cardiac measurements at the initial echocardiogram was significantly different between HLHS variant and normal cases. In the 69 fetuses ultimately diagnosed with HLHS variant, but not in the 202 normals, the Z-scores of all measured left heart structures decreased progressively between the first and the last prenatal echocardiograms (P < 0.01). CONCLUSIONS: The majority of the fetuses with cardiac asymmetry at 18-22 weeks have a good outcome. A minority of them progress to develop HLHS variant with advancing gestation.

Transthoracic echocardiography in pediatric intensive care: impact on medical and surgical management.

OBJECTIVES: Although transthoracic echocardiography is commonly performed in the PICU, its utility is not specifically known. The purpose of this investigation was to evaluate the clinical impact of echocardiography in the PICU in terms of frequency of unanticipated findings and the frequency and nature of clinical management changes attributed to the results of echocardiography. DESIGN: Prospective cohort study. SETTING: Nineteen-bed combined medical-surgical-cardiac PICU at a tertiary care children's hospital. PATIENTS: All patients in PICU undergoing transthoracic echocardiography. INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Data collected included echocardiography indications, pre-echocardiography clinical assessment of anticipated echocardiography findings, height, weight, primary diagnosis, age, and urgency (stat vs routine) of echocardiography. Input of the attending care team (intensivist, cardiologist, and/or cardiovascular surgeon) allowed classification of echocardiography results as either confirming the pre-echocardiography impression, altering the pre-echocardiography clinical impression regarding the indication for which the test was performed, or altering the impression by virtue of new findings unrelated to the specific indication. The nature of the new findings were recorded and categorized. The team recorded clinical management changes made in response to the echocardiography results; the nature of these were listed and categorized. Echocardiograms (n = 416) were performed in 132 patients. Of these, 244 echocardiograms (59%) were ordered on male patients, 31% were under 30 days old, median age was 103 days, 379 (91%) had a primary cardiac diagnosis, and 92 (22%) were ordered stat. Sixty-three percent of echocardiograms confirmed and 24% altered the pre-echocardiography impression regarding the indication for the echocardiography; 13% introduced new findings unrelated to the indication. Cardiac surgical revision was the management change required in 26 patients (6.3%). Stat echocardiography was more likely to alter the pre-echocardiography assessment than routine echocardiography (p < 0.001). Management changes were more commonly associated with stat echocardiograms (p = 0.002) and those with new unexpected findings (p < 0.001) but had no demonstrable association with age less than 30 days (p = 0.332). CONCLUSIONS: Unanticipated echocardiography results are common in the PICU, and they often alter the clinical impressions that prompted the echocardiogram or introduce new findings unrelated to the reason for which the echocardiogram was recorded. Clinical management changes attributable to echocardiography findings are frequent in the PICU, including occasional surgical intervention. Echocardiography adds diagnostic value and contributes to the management approach in the PICU, accounting for its frequent use.

Circulating microRNAs as biomarkers of retinal toxicity.

Despite of the attrition due to retinal toxicity during drug development there are no early reliable predictive biomarkers of retinal toxicity and this is increasingly becoming a concern. Thus far, in pharmacology and toxicology the technologies for assessing retinal side effects are limited to inconvenient visual behavioral tests, invasive electroretinograms or terminal histopathology. To address the lack of convenient early predictive retinal toxicity biomarkers, we explored a set of potential novel retinal enriched miRNAs in rats ex vivo and in vivo with known retinal toxicant pan-CDK inhibitors to assess circulating plasma miRNAs in rats and non-retinal toxicants as controls. Rats were administered a single intravitreal (IVT) injection and blood samples were collected pre-dose, various time points post-dose and then analyzed for five retinal enriched miRNAs (miR-96, miR-124a, miR181a, miR-182 and miR-183) by qRT-PCR. Ophthalmic exam, electroretinogram and histopathology were performed as confirmatory tests. All five miRNAs tested in retinal explants culture were highly expressed after pan-CDK inhibitor treatment. In vivo the pan-CDK inhibitors caused elevations of miR-96, miR-124a and miR-183 in blood. These results highly correlated with ocular exam, electroretinograms and microscopic findings. Comparatively, there were no changes in miRNA levels, electroretinograms, or histopathology in the negative control treatment groups. Although these miRNAs need additional confirmatory evaluation whether they truly predict retinal toxicity prior to clinical observations and histopathology, these results provide promise for further testing using additional retinal toxicants.

Impaired fetal myocardial deformation in intrahepatic cholestasis of pregnancy.

OBJECTIVES: To investigate changes in fetal myocardial deformation in intrahepatic cholestasis of pregnancy. METHODS: Patients with intrahepatic cholestasis of pregnancy were divided into 2 groups according to the total maternal serum bile acid concentration: mild cholestasis (10-40 µmol/L) and severe cholestasis (>40 µmol/L). Fetal echocardiography and velocity vector imaging were performed on women with cholestasis and control patients. The left ventricular global longitudinal strain and strain rate were measured. Clinical characteristics, maternal serum bile acid levels, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in umbilical vein blood were compared between groups. The relationships among fetal myocardial deformation, maternal total bile acids, and cord NT-proBNP were analyzed. RESULTS: Twenty women with mild cholestasis, 20 with severe cholestasis, and 40 control patients were enrolled. There were no significant differences in maternal and gestational ages between the case and control groups. Maternal bile acids and NT-proBNP were significantly higher in fetuses of mothers with cholestasis than control fetuses. The left ventricular longitudinal strain (-10.56% ± 1.83% versus -18.36% ± 1.11%; P < .01), systolic strain rate (-1.63 ± 0.18 versus -2.04 ± 0.18 secondsz(-1); P < .01), and diastolic strain rate (1.37 ± 0.18 versus 1.83 ± 0.14 seconds(-1); P < .01) were significantly decreased in fetuses with severe cholestasis compared with control fetuses. There were positive correlations between fetal myocardial deformation and maternal total bile acids (r = 0.705, 0.643, and 0.690, respectively; P < .01) and between myocardial deformation and NT-proBNP (r = 0.672, 0.643, and 0.647; P < .01). CONCLUSIONS: Fetal myocardial deformation is impaired in severe intrahepatic cholestasis of pregnancy. Further investigation is needed to determine whether fetal echocardiography and velocity vector imaging can help predict which fetuses of mothers with cholestasis are likely to have poor outcomes.

[Fetal pulmonary venous Doppler flow patterns in hypoplastic left heart syndrome].

OBJECTIVE: To discuss the value of fetal pulmonary venous Doppler flow patterns in hypoplastic left heart syndrome (HLHS). METHODS: Forty-six HLHS and 180 normal singleton fetuses at 24+0 to 37+6 weeks of gestation were enrolled in this study. The blood flow of pulmonary vein (PV) was detected by color Doppler ultrasound. The systolic wave of ventricle (S-wave), diastolic wave of ventricle (D-wave), atrial contraction wave (A-wave) and S/D ratio of PV were measured. The statistical difference in the above parameters between HLHS and normal fetuses was compared. The diagnosis was also confirmed by autopsy in still birth or postnatal follow-up when the baby was alive. RESULTS: The PV blood flow in HLHS fetuses had a high possibility of reversed A wave, and the velocity of S wave and S/D ratio were higher than the matched normal controls (P<0.001). There were 3 types of PV blood flow patterns among all fetuses with HLHS. Both the cases with right to left shunt through foramen ovale (FO) and the cases with restricted left to right shunt at FO showed the triphasic patterns of PV with antegrade S wave, D wave and retrograde A wave. However, the latter had a higher velocity of retrograde A wave (P<0.001), lower D wave (P<0.001), and obviously elevated S wave and S/D ratio (P<0.001). The cases with intact interatrial septum showed short and apparent pulsatile back and forth blood flow in the PV, which displayed as absence of D wave. CONCLUSION: The 3 types of PV blood flow patterns in the fetuses with HLHS reflect the severity of hypertension in the left atrium, which is extremely vital for the prognosis and the perinatal treatment plan.

[3-vessel subsequence view in prenatal screen and diagnosis of fetal congenital heart disease].

OBJECTIVE: To investigate the clinical significance of 3-vessel subsequence view in prenatal screening and diagnosis of fetal congenital heart disease. METHODS: The 3-vessel subsequence view of 231 fetuses with congenital heart disease was obtained with Sequoia 512, Voluson 730 and E8 color Doppler ultrasonographic diagnostic system. RESULTS: Of the 231 consecutive fetuses with congenital heart defects (CHD), 169 (73%) had at least 1 abnormality on the 3-vessel subsequence view. When ventricl septal defects and so on were excluded, the detection rate increased to 91%. Some defects had several abnormalities visualized at the 3-vessel subsequence view. CONCLUSION: The 3-vessel subsequence view has high detection rate in identifying the presence of CHD.