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Objective: To compare the cardiac output (CO) and ejection fraction (EF) of the heart of male and female fetuses obtained by 3D-ultrasonography using spatio-temporal image correlation (STIC)., Methods: We conducted a cross-sectional study with 216 normal fetuses, between 20 and 34 weeks of gestation, 108 male and 108 female. Ventricular volumes at the end of systole and diastole were obtained by STIC, and the volumetric assessments performed by the virtual organ computer-aided analysis (VOCAL) rotated 30º. To calculate the DC used the formula: DC = stroke volume / fetal heart rate, while for the FE used the formula: EF = stroke volume / end-diastolic volume. The DC (combined male and female) and EF (male and female) were compared using the unpaired t test and ANCOVA. Scatter plots were created with the percentiles 5, 50 and 95., Results: The average of DC combined, DC left, DC right, FE right and FE left, male and female were 240.07 mL/min, 122.67 mL/min, 123.40 mL/min, 72.84%, 67.22%, 270.56 mL/ min, 139.22 mL/min, 131.34 mL/min, 70.73% and 64.76% respectively, without statistical difference (P> 0.05)., Conclusions: The fetal CO and EF obtained by 3Dultrasonography (STIC) showed no significant difference in relation to gender.

Background and Purpose: Cannabinoid (CB) receptor agonists have potential utility as anti-inflammatory drugs in chronic immune inflammatory diseases. In the present study, we characterized the signal transduction pathways affected by CB(2) receptors in quiescent and lipopolysaccharide (LPS)-stimulated murine microglia., Experimental Approach: We examined the effects of the synthetic CB(2) receptor ligand, JWH-015, on phosphorylation of MAPKs and NO production., Key Results: Stimulation of CB(2) receptors by JWH-015 activated JNK-1/2 and ERK-1/2 in quiescent murine microglial cells. Furthermore, CB(2) receptor activation increased p-ERK-1/2 at 15 min in LPS-stimulated microglia. Surprisingly, this was reduced after 30 min in the presence of both LPS and JWH-015. The NOS inhibitor L-NAME blocked the ability of JWH-015 to down-regulate the LPS-induced p-ERK increase, indicating that activation of CB(2) receptors reduced effects of LPS on ERK-1/2 phosphorylation through NO. JWH-015 increased LPS-induced NO release at 30 min, while at 4 h CB(2) receptor stimulation had an inhibitory effect. All the effects of JWH-015 were significantly blocked by the CB(2) receptor antagonist AM 630 and, as the inhibition of CB(2) receptor expression by siRNA abolished the effects of JWH-015, were shown to be mediated specifically by activation of CB(2) receptors., Conclusions and Implications: Our results demonstrate that CB(2) receptor stimulation activated the MAPK pathway, but the presence of a second stimulus blocked MAPK signal transduction, inhibiting pro-inflammatory LPS-induced production of NO. Therefore, CB(2) receptor agonists may promote anti-inflammatory therapeutic responses in activated microglia., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Objectives: The purpose of this study was to determine reference values for the length and area of the fetal corpus callosum between 20 and 33 weeks' gestation using 3-dimensional sonography., Methods: A cross-sectional study was performed in 293 healthy pregnant women between 20 and 33 weeks' gestation. The length and area of the corpus callosum were obtained via the transfontal view with the metopic suture as an acoustic window using 3-dimensional sonographic aquisitions. Linear and weighted polynomial regression models were used, which were adjusted by residual analysis and the R(2) determination coefficient. Intraobserver and interobserver reproducibilities were analyzed by an intraclass correlation coefficient., Results: The mean corpus callosum length ± SD varied from 19.52 ± 2.24 to 40.36 ± 2.87 mm, whereas the mean area varied from 0.44 ± 0.11 to 1.47 ± 0.21 cm(2) at 20 and 33 weeks, respectively. The length and area were highly correlated with gestational age: corpus callosum length = -52.41 + 4.71 × gestational age - 0.06 × gestational age(2) (R(2) = 0.868); and corpus callosum area = -2.47 + 0.16 × gestational age - 0.000037 × gestational age(2) (R(2) = 0.765). The intraobserver and interobserver reproducibilities were excellent, with intraclass correlation coefficients of 0.98 and 0.94 for the length and 0.99 and 0.90 for the area, respectively., Conclusions: Reference values for the length and the area of the fetal corpus callosum between 20 and 33 weeks' gestation were determined with high reproducibility.

Objectives: The aim of this study was to establish nomograms for fetal stroke volume (SV), cardiac output (CO), and ejection fraction (EF) using four-dimensional ultrasound with spatio-temporal image correlation (STIC) modality., Methods: The fetal heart was scanned using STIC modality, starting with classic four-chamber view plane, during fetal quiescence with abdomen uppermost, at an angle of 20-30°, without color Doppler flow mapping. In post-processing virtual organ, computer-aided analysis technique was used to obtain a sequence of six sections of each ventricular volume in end-systolic volume (ESV) and end-diastolic volume (EDV). The SV (SV = EDV-ESV), CO (CO = SV × fetal heart rate), and EF (EF = SV/EDV) for each ventricle were then calculated. Intra- and interobserver agreement were then calculated., Results: Two hundred sixty-five fetuses, ranging in gestational age (GA) from 20 to 34(+6) weeks, were included in the study. The left and right SV and CO increased exponentially with gestation and EF remained fairly stable through gestational. Mean left and right SV increased from 0.211 ml and 0.220 ml at 20 weeks to 1.925 ml and 2.043 ml, respectively, at 34 weeks. Mean left and right CO increased from 30.25 ml/min and 31.52 ml/min at 20 weeks to 268.49 ml/min and 287.80 ml/min, respectively, at 34 weeks. Both left and right mean EF remained constant at around 0.63 with advancing GA. Nomograms were created for LSV, RSV, LCO, RCO, LEF, and REF vs. gestational age. Intra- and interobserver agreement reached 95%., Conclusions: Four-dimensional ultrasound using STIC represents a simple and reproducible method for estimating fetal cardiac function. STIC seems to overcome many of the pitfalls of conventional ultrasound methods and has the potential to become the method of choice.

Adenosine is a ubiquitous signaling molecule whose physiological functions are mediated by its interaction with four G-protein-coupled receptor subtypes, termed A(1), A(2A), A(2B) and A(3). As a result of increased metabolic rates, this nucleoside is released from a variety of cells throughout the body in concentrations that can have a profound impact on vasculature and immunoescape. However, as high concentrations of adenosine have been reported in cancer tissues, it also appears to be implicated in the growth of tumors. Thus, full characterisation of the role of adenosine in tumor development, by addressing the question of whether adenosine receptors are present in cancer tissues, and, if so, which receptor subtype mediates its effects in cancer growth, is a vital research goal. To this end, this review focuses on the most relevant aspects of adenosine receptor subtype activation in tumors reported so far. Although all adenosine receptors now have an increasing number of recognised biological roles in tumors, it seems that the A(2A) and A(3) subtypes are the most promising as regards drug development. In particular, activation of A(2A) receptors leads to immunosuppressive effects, which decreases anti-tumoral immunity and thereby encourages tumor growth. Due to this behavior, the addition of A(2A) antagonists to cancer immunotherapeutic protocols has been suggested as a way of enhancing tumor immunotherapy. Interestingly, the safety of such compounds has already been demonstrated in trials employing A(2A) antagonists in the treatment of Parkinson's disease. As for A(3) receptors, the effectiveness of their agonists in several animal tumor models has led to the introduction of these molecules into a programme of pre-clinical and clinical trials. Paradoxically, A(3) receptor antagonists also appear to be promising candidates in human cancer treatment of regimes. Clearly, research in this still field is still in its infancy, with several important and challenging issues remaining to be addressed, although purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Early detection of septal changes such as septal hypertrophy commonly present in fetuses of diabetic mothers would help reduce the high rates of infant mortality., Objective: Determine reference ranges for the fetal ventricular septal area through three-dimensional ultrasound (US3D) using the STIC method (Spatio-Temporal Image Correlation)., Methods: We conducted a cross-sectional study with 69 pregnant women between the 18th and 33rd weeks of pregnancy. We used as a reference the four-chamber plane with the ROI (Region of Interest) positioned from the ventricles; the septum area were manually marked. To assess the correlation of the interventricular septum area with gestational age (GA), we constructed scatter plots and calculated Pearson's correlation coefficient (r), and the adjustment was performed by the coefficient of determination (R²). We calculated averages, medians, standard deviations (sd), as well as maximum and minimum values. To calculate the intraobserver reproducibility, we used the intraclass correlation coefficient (ICC). The interventricular septum thickness was measured and it was correlated with gestational age and the septal area rendered in 52 patients using the ICC., Results: The interventricular septum area was highly correlated with gestational age (r = 0.81), and the average increased from 0.47 cm² in the 18th week to 2.42 cm² in the 33rd of gestation. The intraobserver reproducibility was excellent with ICC = 0.994. No significant correlation was observed between the interventricular septum measurement and the GA (R² = 0.200), as well as there was no correlation with the septal area rendered with ICC = 0.150., Conclusion: Reference intervals for the interventricular septum area between the 18th and the 33rd pregnancy week were determined to be highly reproducible.

Purpose: to evaluate the areas of the atrioventricular valves (tricuspid and mitral) of normal fetuses by the use of three-dimensional ultrasound (3DUS) and the spatiotemporal image correlation (STIC) method., Methods: a cross-sectional study was conducted on 141 women between the 18th and the 33rd week of pregnancy. Cardiac volumes were measured with a volumetric transabdominal transducer attached to the Voluson 730 Expert equipment. The four chamber plane was used as reference, with the region of interest (ROI) positioned from the ventricles, and the area of the valves was obtained manually. To determine the correlation of the areas with gestational age, scatter plots were constructed and the Pearson correlation coefficient (r) was calculated. Means, medians, standard deviations (SD) and maximum and minimum values were calculated. The simple linear regression model was used to determine reference ranges of valve areas according to the gestational age by the Altman method, with the level of significance set at p<0.05. To calculate the intraobserver reproducibility, we used the intraclass correlation coefficient (ICC) and the Bland-Altman graph., Results: the mitral and tricuspid valve areas were correlated to the gestational age (r=0.80 for the tricuspid and r=0.79 for the mitral valve) and the mean value of the tricuspid and mitral valves increased from 0.22 ± 0.10 cm² and 0.23 ± 0.10 cm² on the 18th week to 0.92 ± 0.29 cm² and 1.08 ± 0.41 cm² on the 33rd of pregnancy, respectively. The intraobserver reproducibility resulted in an ICC=0.993 (95%CI 0.987; 0.996) and the mean difference was 0.01 cm² (SD ± 0.2 cm² and CI95% ± 0.4 cm²)., Conclusion: reference intervals for the areas of the mitral and tricuspid valve between the 18th and the 33rd week of gestation were determined and proved to be highly reproducible.

The thermodynamic parameters DeltaG degrees , DeltaH degrees and DeltaS degrees of the binding equilibrium of agonists and antagonists at cannabinoid CB(1) and CB(2) receptors were determined by means of affinity measurements at different temperatures and van't Hoff plots were constructed. Affinity constants were measured on CHO cells transfected with the human CB(1) and CB(2) receptors by inhibition assays of the binding of the cannabinoid receptor agonist [(3)H]-CP-55,940. van't Hoff plots were linear for agonists and antagonists in the temperature range 0-30 degrees C. The thermodynamic parameters for CB(1) receptors fall in the ranges 17< or =DeltaH degrees < or =59 kJ/mol and 213< or =DeltaS degrees < or =361 kJ/mol for agonists and -52< or =DeltaH degrees < or =-26 kJ/mol and -12< or =DeltaS degrees < or =38 kJ/mol for antagonists. The thermodynamic parameters for CB(2) receptors fall in the ranges 27< or =DeltaH degrees < or =48 kJ/mol and 234< or =DeltaS degrees < or =300 kJ/mol for agonists and -19< or =DeltaH degrees < or =-17 kJ/mol and 43< or =DeltaS degrees < or =74 kJ/mol for antagonists. Collectively, these data show that agonist binding is always totally entropy-driven while antagonist binding is enthalpy and entropy-driven, indicating that CB(1) and CB(2) receptors are thermodynamically discriminated. These data could give new details on the nature of the forces driving the CB(1) and CB(2) binding at a molecular level. Enthalpy, entropy, free energy and binding affinity for each ligand to its receptor can all be assessed and therefore the optimal binding profile discovered. Carrying out these binding investigations as early as possible in the discovery process increases the probability that a lead compound will become a successful pharmaceutical compound.

Objective: To evaluate the concordance between two-dimensional ultrasonography (2DUS), three-dimensional ultrasonography (3DUS) and magnetic resonance imaging (MRI) in the assessment of lung volume in fetuses with urinary tract malformations (UTM)., Methods: This was a cross-sectional study involving 12 pregnancies between 19 and 34 weeks, with various fetal UTM. Pulmonary volume was obtained by 2DUS using the following equation: total lung volume = [right lung antero-posterior diameter (X) x transverse diameter (Y) x cranial-caudal diameter x 0.152 + left lung (X1) x (Y1) x (Z1) x 0.167]. Pulmonary volume by 3DUS was obtained using the virtual organ computer-aided analysis (VOCAL) method with a 30 degrees (VOL30), 18 degrees (VOL18) and 12 degrees (VOL12) rotation. A fast sequence of transverse lung section was also obtained by MRI. The intraclass correlation coefficient was used to evaluate the correlation between the three methods. The paired student t-test was used to compare the means., Results: There was a strong correlation between the three methods, and the highest correlations were between MRI and VOL18 for the right (ICC = 0.913) and left (ICC = 0.947) lungs. A strong correlation was also found between the lung volumes obtained through MRI and VOL12 as well as VOL18 (p = 0.544 and 0.286, respectively). However, for the left lung there was only a correlation between MRI and VOL12 (p = 0.49)., Conclusions: There is a good concordance between 3DUS (VOL12) and MRI in the evaluation of lung volume in fetuses with UTM.

Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often have abnormal growth factor and cytokine profiles. Thus, serum levels of interleukin-8 (IL-8) are elevated in patients with malignant melanoma. In addition to IL-8, aggressive melanoma cells secrete, through its transcriptional regulator hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), which promotes angiogenesis and metastasis of human cancerous cells. Whether these responses are related to adenosine, a ubiquitous mediator expressed at high concentrations in cancer and implicated in numerous inflammatory processes, is not known and is the focus of this study. We have examined whether the DNA-damaging agents etoposide (VP-16) and doxorubicin can affect IL-8, VEGF, and HIF-1 expressions in human melanoma cancer cells. In particular, we have investigated whether these responses are related to the modulation of the adenosine receptor subtypes, namely, A(1), A(2A), A(2B), and A(3). We have demonstrated that A(2B) receptor blockade can impair IL-8 production, whereas blocking A(3) receptors, it is possible to further decrease VEGF secretion in melanoma cells treated with VP-16 and doxorubicin. This understanding may present the possibility of using adenosine antagonists to reduce chemotherapy-induced inflammatory cytokine production and to improve the ability of chemotherapeutic drugs to block angiogenesis. Consequently, we conclude that adenosine receptor modulation may be useful for refining the use of chemotherapeutic drugs to treat human cancer more effectively.

We assessed the vascular indices of the anterior territory of the middle cerebral artery (MCA) in normal pregnancies using 3-D power Doppler (3DPD). A cross-sectional study was carried out on 90 normal pregnancies between 24 and 35 weeks. All examinations were performed by a single operator using a volumetric transducer. The anterior territory of the MCA was scanned and the volumes were captured using 3DPD. The sphere mode of the VOCAL program was used to calculate the following vascular indices: vascularization index (VI), flow index (FI) and vascularization and flow index (VFI). Models of polynomial regression and Pearson's correlation coefficient were used to evaluate the correlation between gestational age (GA) and the vascular indices. The 3DPD vascular indices had a low correlation with gestational age (VI - r = 0.324, p = 0.002; FI - r = 0.375, p < 0.001; VFI - r = 0.374, p < 0.001). There was a low correlation between GA and the 3DPD vascular indices of the anterior territory of the MCA.

Objective: To establish normative data for the peak systolic velocity of the middle cerebral artery (MCA-PSV) of fetuses in the second half of pregnancy using multiples of the median and percentile reference range., Methods: A cross-sectional study was performed in 90 healthy fetuses at between 23 and 35 weeks of gestation. A bi-dimensional axial scan of the brain, including the thalami and cavitas septi pellucidi was obtained. The circle of Willis was visualized using color flow mapping. Pulsed-wave Doppler velocimetry of the MCA was performed close to the artery's origin, with a beam-vessel angle below 20 degrees . A table with the multiples of the median (MoM) of the MCA-PSV for each gestational age was generated and Pearson's correlation coefficient (r) was calculated. Regression modeling across gestational age was performed to obtain the reference values., Results: There was a strong correlation between the MCA-PVS and gestational age (r = 0.70; p < 0.001). Values for the MCA-PSV for the following MoM were calculated: 1.0, 1.29, 1.50, and 1.55. The MCA-PSV 2.5(th) and 97.5(th) centiles ranged from 24.33 cm(2)/s to 78.36 cm(2)/s, respectively, between weeks 23 and 35., Conclusions: A nomogram for the fetal MCA-PSV during the second half of pregnancy was generated.

Frequent coffee consumption has been associated with a reduced risk of colorectal cancer in a number of case-control studies. Coffee is a leading source of methylxanthines, such as caffeine. The induction of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key regulator of this process. In this study, we investigated the effects of caffeine on HIF-1 protein accumulation and on VEGF and IL-8 expression in the human colon cancer cell line HT29 under hypoxic conditions. Our results show that caffeine significantly inhibits adenosine-induced HIF-1alpha protein accumulation in cancer cells. We show that HIF-1alpha and VEGF are increased through A3 adenosine receptor stimulation, whereas the effects on IL-8 are mediated via the A2B subtype. Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression. The mechanism of caffeine seems to involve the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and Akt, leading to a marked decrease in adenosine-induced HIF-1alpha accumulation, VEGF transcriptional activation, and VEGF and IL-8 protein accumulation. From a functional perspective, we observe that caffeine also significantly inhibits the A3 receptor-stimulated cell migration of colon cancer cells. Conditioned media prepared from colon cells treated with an adenosine analog increased human umbilical vein endothelial cell migration. These data provide evidence that adenosine could modulate the migration of colon cancer cells by an HIF-1alpha/VEGF/IL-8-dependent mechanism and that caffeine has the potential to inhibit colon cancer cell growth.