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BACKGROUND: Lipedema is a chronic disease marked by symmetric enlargement of painful nodular and fibrotic adipose tissue, predominantly affecting the limbs. Since there is no specific test or biomarker for this condition, years often pass before the diagnosis of lipedema is established for the first time, thereby causing psychosocial distress, including depression, eating disorders, and social isolation. Over the last few years several advanced Doppler–based technologies have been developed to visualize slow flow blood vessels and superficial microvascular architecture undetectable by traditional color Doppler flow imaging (CDFI). OBJECTIVE: The aim of this study was to evaluate the superficial microvascular anatomy in lipedema patients compared to healthy controls and investigate the clinical significance of the Ultra Micro Angiography (UMA) technology in the diagnosis of lipedema. This new technique may contribute to reduce the diagnostic delay and, eventually, establish and guide treatment strategies toward a better therapeutic outcome in lipedema patients. METHODS: 25 patients with lipedema and ten healthy controls with no history of lipedema were included in this study. All ultrasound examinations were performed on a novel high-performance ultrasound system (Resona R9/Mindray) using CDFI and the UMA technique. RESULTS: In all of the patients, Ultra Micro Angiography achieved the excellent visualization of microvascular structures, revealing that most lipedema patients showed grade 3 (n = 13) or grade 2 (n = 8) flow. UMA was superior to CDFI for depicting the microvascular structures. CONCLUSIONS: Here we show that UMA imaging characterizes the subcutaneous microvasculature with an unprecedented accuracy. The method has the advantage of being sensitive to small, slow-flowing vessels. This allows for the assessment of the course of vessels and vascular pathologies in great detail. Thus, UMA as a non-invasive diagnostic method can improve diagnostic accuracy in lipedema. [ABSTRACT FROM AUTHOR]

Building a precise alternative neurotoxicological test is of great importance to respond to societal and ethical requirements. In this study, a new developmental neurotoxicity test (DNT) was established with the human neural progenitor cell line. ReNcell CX cells were exposed to neurotoxic chemicals (aphidicolin, hydroxyurea, cytosine arabinoside, 5-fluorouracil, and ochratoxin A) or non-neurotoxic chemicals (sodium gluconate, sodium bicarbonate, penicillin G, and saccharin). Propidium iodide (PI) was used to evaluate cell viability. BrdU and Ki-76 were employed to determine cell proliferation. Based on the cell viability and proliferation, mathematical models were built by linear discriminant analysis. Furthermore, the neurotoxic-considered chemicals inhibited cell cycle progression at the protein level, supporting the biomolecular rationale for the predictive model. Overall, these results show that the new test method can be used to determine the potential developmental neurotoxicants or new drug candidates. [ABSTRACT FROM AUTHOR]

Transcellular calcium transport is an essential activity in mineralized tissue formation, including that in nervous systems. Dysregulation of Ca2+ homeostasis can induce excitotoxicity and neurodegeneration in the central nervous system. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is most abundant in the brain and has a critical role in the transport of intracellular calcium across the cell membrane. However, the roles of Nckx3 in neuron development and function remain unreported. Herein, we examined the behaviors of Nckx3-knock-out mice at the age of six weeks. Detailed behavioral analyses showed Nckx3-/- mice exhibited an increase in moving distances in the open field test. Additionally, the rotarod test revealed motor learning defects in Nckx3-/- mice. Both Nckx3+/- and Nckx3-/- mice also exhibited deficits in sociability and social novelty preference. Furthermore, Nckx3-/- mice displayed increased depression-related behavior. However, there was no significant change in cognition function detected in Nckx3-/- mice. This study demonstrates that NCKX3 is involved in behavior and neuronal function. [ABSTRACT FROM AUTHOR]

The embryoid body test (EBT) is a developmental toxicity test method that measures the size of embryoid bodies (EBs) and the viability of mouse embryonic stem cells (mESCs) and fibroblasts (3T3 cells). The previous pre-validation study confirmed the high accuracy (above 80%) of EBT using 26 coded test chemicals. This second-phase validation study assessed the inter-laboratory reproducibility (5 chemicals in common) and predictive capacity (10 chemicals in each laboratory) test using the coded test chemicals at three laboratories. For the prediction model, the accuracy is increased when more data is accumulated. Therefore, we updated the prediction model and analyzed the results of the second year with the newly created-prediction model. Statistical analysis of the inter-laboratory reproducibility test results indicated that accuracy, sensitivity, and specificity were 87%, 78%, and 100%, respectively. The results of the statistical analysis of the predictive capacity test showed an accuracy of 80%, sensitivity of 78%, and specificity of 81%. In conclusion, the EBT can accurately classify various embryotoxicants within a short period and with relatively little effort. Therefore, EBT can be used as a good way to test developmental toxicity. [ABSTRACT FROM AUTHOR]

The present study investigated whether melatonin influences the expression/oligomerization of amylin with endoplasmic reticulum (Er) stress in rat insulinoma iNs-1E cells. No change in cell survival after exposure to thapsigargin- and tunicamycin-combined melatonin treatment or melatonin-only treatment was observed when compared with the normal control cells. With thapsigargin-only or combined tunicamycin-melatonin treatments, phosphorylation of extracellular signal-regulated kinase (ErK) was significantly increased compared with control and melatonin-only treatments. a significant increase was observed in the levels of Er stress markers, namely, phosphorylated inositol-requiring protein 1a (p-irE1a), ccaat enhancer binding proteins (c/EBp)-homologous protein, p-eukaryotic translation initiation factor 2a and cleaved caspase-12, in the thapsigargin-combined melatonin-treated cells as compared with the tunicamycin-combined or only melatonin treatment. the melatonin-only treatment resulted in increased levels of amylin expression/oligomerization in 15-25 kda and insulin proteins, compared with the thapsigargin- and tunicamycin-combined melatonin treatments. treatment with Er stress inhibitor 4-phenylbutyric acid (4-pBa) did not suppress amylin expression/oligomerization or insulin production with thapsigargin or tunicamycin treatment. levels of cleaved caspase-12 were significantly decreased in the thapsigargin- or tunicamycin-4-pBa combination treatments. therefore, whether melatonin regulates the amylin expression/oligomerization in thapsigargin- or tunicamycin-combined with Bafilomycin a1 (autophagy inhibitor) or MG132 (proteasome inhibitor) treatments were investigated. amylin expression/oligomerization with melatonin treatment was significantly decreased in the thapsigargin- or tunicamycin-combined Bafilomycin a1 or MG132 treatments. since these outcomes are involved in cell viability, they indicate that increased cell death leads to decreased amylin expression/oligomerization, however, the effects of melatonin treatment on amylin expression/oligomerization induce proliferation of pancreatic β cells and improve the cellular functions of pancreatic β cells. [ABSTRACT FROM AUTHOR]

Endocrine-disrupting chemicals (EDCs) have structures similar to steroid hormones and can interfere with hormone synthesis and normal physiological functions of reproductive organs. For example, sex steroid hormones influence calcium signaling of the cardiac muscle in early embryo development. To confirm the effect of progesterone (P4), octyl-phenol (OP), and bisphenolA(BPA) on early differentiation of mouse embryonic stem cells(mESCs) into cardiomyocytes, mESCs were treated with P4, OP, and BPA two days after attachment and media were replaced every two days. In addition, cells were treated with mifepristone (RU486), a synthetic steroid that has an affinity for progesterone receptor (Pgr), for one day starting on day 11. Beating ratio was decreased with P4, OP, and BPA treatment. The Pgr mRNA level was significantly increased in the P4-, OP- and BPA-treated groups. However, the mRNA level of the calcium channel gene (Trpv2), contraction-related genes (Ryr2, Cam2, and Mylk3) and cardiac development and morphogenesis genes (Rbp4, Ly6e, and Gata4) were significantly decreased in the P4-, OP-, and BPA-treated groups. Interestingly, treatment with RU486 rescued the altered calcium channel gene, contraction-related genes, and cardiac development and morphogenesis genes. P4, OP, and BPA treatments reduced the intracellular calcium level. Taken together, these results indicate that EDCs (OP and BPA) has a structure similar to that of endogenous steroid hormones such as progesterone and estrogen, and OP and BPA act like progesterone to inhibit and disrupt cardiomyocyte differentiation of mESCs. [ABSTRACT FROM AUTHOR]

Dexamethasone inhibits mucin secretion considering the primary option for treating acute asthma exacerbation. However, the mechanism underlying dexamethasone-induced decreased in mucosecretion is unclear. Recent studies have reported that dexamethasone exerts an inhibitory effect on mucosecretion in the lung by modulating the expression of calcium processing genes. However, the expression of the calcium processing genes in the trachea is not examined yet. Thus, the present study is the first to report the localization of calcium processing proteins such as transient receptor potential vanilloid-4 (Trpv4), transient receptor potential vanilloid-6 (Trpv6), calbindin-D9k (CaBP-9k) and plasma membrane Ca2+-ATPase 1 (Pmca1) in the mouse trachea and their glucocorticoid-induced response. In this study, mice were subcutaneously injected with dexamethasone for 5 days, and their tracheal samples were collected by dividing the trachea into the cervical, and thoracic sections based on its anatomical structure. The localization of TRPV4, TRPV6, CaBP-9k, and PMCA1 proteins was detected in the tracheal epithelium, submucosal glands, cartilages and muscles. Dexamethasone treatment downregulated the mRNA expression of the four calcium processing genes and mucin producing genes. The dexamethasone-induced decrease in the secretion of mucosubstances in the trachea was determined by performing Alcian blue-periodic acid-Schiff staining. Thus, the findings of the present study suggest that glucocorticoids simultaneously can regulate the expression of calcium processing genes and tracheal mucosecretion. [ABSTRACT FROM AUTHOR]

Ultrasound contrast agents (USCA) allows the dynamic detection of blood flow of both the macro and microvasculature. An obvious prerequisite for USCAs is the unhindered passage of clinically relevant dose levels through the microcirculation especially of the lungue, where they have to pass capillaries with diameters of around 4 µ m. While smaller microbubbles rapidly passed through the microcirculation along with the red blood cells, larger microbubbles, however, were observed to coalesce and interrupt the blood flow. Whether this might influence the tissue oxygen tension is unclear up to now. To examine this question a bolus of 2.4 ml SonoVue™ was injected into the suprarenal aorta at a flow rate of 10 ml/s (a dosage usually applied in the clinic). The pO2 in the outer medulla of the kidneywas continuously measured using a flexible pO ü microcatheter. In addition, the SonoVue™ injection and its passage through the renal vasculature were documented by the CEUS technology to assess whether the microbubbles passed the kidney. The study revealed that SonoVue™ induced no changes of the mean oxygen partial pressure in the outer medulla which confirms that these microbubbles on their way through the medullar capillaries did not hinder the co-flow of blood through the renal microvessels in a big animal model with a renal morphology and function comparable to human kidneys. These results demonstrate that the CEUS diagnostic itself did not influence the system to be examined which is a most important prerequisite for any diagnostic method. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare contrast-enhanced computed tomography (CT) and contrast-enhanced ultrasound (CEUS) for the quantitative evaluation of an ablation defect following radiofrequency ablation of malignant liver lesions in a prospective study. MATERIALS AND METHODS: 22 radiofrequency ablations of malignant liver tumors were performed. The ablation defects were then measured and evaluated by two independent examiners via contrast-enhanced computed tomography (CT) and contrast-enhanced ultrasound (CEUS) using a 1--5MHz multifrequency convex ultrasound transducer (LOGIQ E9, GE) with respect to the short-axis diameter, the long-axis diameter, and the area. RESULTS: Quantitative evaluation of ablation defects is possible with both contrast-enhanced CT and CEUS. The average long-axis diameter was 47.1mm (±11.08;±23,5%) on CEUS and 56.48mm (±14.14;±25,0%) on CT; the short-axis diameterwas 39.72mm(±11.14;±28,05%) on CEUS and 40.27mm(±10.50;±26,07%) on CT; the areawas 1439.82 mm² (±678.57;±47,13%) on CEUS and 2392.68 mm² (1147.67;±48,0%) on CT. On average, ablation defects are assessed to be larger on CT than on CEUS. A significant correlation between the modalities could not be achieved for all measurement axes. CONCLUSION: CEUS can be used for the postinterventional detection and evaluation of ablation defects. However, these are always assessed to be larger on contrast-enhanced CT than CEUS. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Irreversible electroporation (IRE) is a novel focal ablation technique applicable for treatment of prostate cancer (PCa).We aim to evaluate imaging findings of T1-weighted contrast-enhanced MRI after percutaneous IRE of low-risk PCa. METHODS:Atotal of 13 male patients underwent IRE of focal low-risk PCa and were included in this analysis. Prostate IRE was conducted using 2-4 electrodes being placed under CT-fluoroscopy guidance. Dynamic contrast-enhanced 3D isotropic fat-saturated T1-weighted MRI (DCE-MRI) was performed 24-72 hours before and 24-72 hours after ablation. RESULTS: Ablated prostate was either homogeneously (8/13 [62%]) or heterogeneously (5/13 [38%]) hypo attenuating. Peripheral contrast enhancement manifesting as a hyper attenuating margin was observed during the arterial (60 sec) (3/13 [23%]) and venous (240 sec) (10/13 [77%]) phase. The ablation defect showed a sharp (8/13 [62%]) or blurry (5/13 [38%]) margin. CONCLUSIONS:The results showa venous peripheral rim enhancement in most of the cases, indicating reactive hyperaemia. The heterogeneous appearance of the defect zone in some cases may be secondary to sustained vascularization. [ABSTRACT FROM AUTHOR]

PURPOSE: To determine the influence of pre-interventionally existing portal vein thrombosis on the ablation success of percutaneous tumor ablation of HCC. MATERIALS AND METHODS: 15 patients with HCC and pre-existing portal vein thrombosis underwent thermal tumor ablation. We retrospectively analyzed the pre- and post-interventionally performed CT and MRI scans in terms of technical success as well as the complication rate. The portal vein thrombosis was classified into segmental, lobar and central thrombus. RESULTS: In 13/15 cases (87%) complete ablation with no evidence of residual tumor tissue was seen 6 weeks after the procedure in contrast-enhanced MRI scans and contrast-enhanced ultrasound (CEUS). No major and 2 minor complications were observed after the ablation procedure. CONCLUSION: Reduced perfusion due to pre-interventionally existing portal vein thrombosis has no significant impact on the ablation success or the complication rate. [ABSTRACT FROM AUTHOR]

PURPOSE: To compare the diagnostic performance of real-time maximum liver capacity (LiMAx) with dynamic contrastenhanced ultrasound (CEUS)-based liver microcirculation. MATERIALS AND METHODS: 23 patients underwent liver function capacity (LiMAx) test and consecutive or previous CEUS examinations. A bolus injection of 1.4 ml sulfur hexafluoride microbubbles was administered for CEUS measurements (1-6 MHz) and quantitative perfusion analysis (TIC) was performed with an integrated perfusion software using stored cineloops. Two perfusion-parameters, time to peak (TtoP) and area under the curve (Area), were evaluated in liver parenchyma and portal vein using TIC analysis. To compare quantification parameters, patients were classified in patients representing a healthy population (LiMAx value >315 µg/kg/h) and those representing patients with liver disease (LiMAx value <315 µg/kg/h). RESULTS: Comparing perfusion parameters derived from portal vein measurements, TtoP and Area were higher in patients with normal liver function TtoP: 25.0±8.4 s, Area: 1483±920 a.u. compared to patients with impaired liver function TtoP: 22.4±14.0 s; Area 1351±1212 a.u. This difference however was not statistically significant (p = 0.52, p = 0.48). In parameters derived from measurements in liver parenchyma TtoPwas higher (38.5±11.3 s) and Areawas lower (999±632 a.u.) in patients with normal liver function compared to patients with impaired liver function (TtoP; 30.6±11.0 s, p = 0.156; Area: 1202±719 a.u.) (p = 0.16, p = 0.56). In a simple linear regression model, none of the perfusion parameters measured in portal vein (TtoP portal, Area portal) and liver parenchyma (TtoP liver, Area liver) correlated significantly with respective LiMAx values (p = 0.194-0.950). CONCLUSION: Within the framework of this study, CEUS-based perfusion parameters were not able to assess severity of liver disease, assessed with LiMAx- test. [ABSTRACT FROM AUTHOR]

AIM: To evaluate the efficiency of intraoperative contrast enhanced ultrasound (Io-CEUS) for assessment of radiofrequency ablation (RFA) during liver tumor surgery. MATERIAL AND METHODS: Retrospective analysis was performed on a total number of 18 patients out of over 500 patients who underwent combined liver tumor surgery and RFAof 27 hepatic tumors between 02/2011 and 12/2016. Io-CEUS was performed by bolus injections of up to 10 ml sulphur hexaflourid microbubbles for diagnostic purposes. To guide the RFA up to 20 ml microbubbles were applied to monitor the procedure and assess the ablation status finally. A fully avascular area or absence of any residual vascularization intratumorally was considered technical success. These findings were correlated to findings of follow-up imaging results (CEUS, MRI, CT) at least 1 up to 40 months (mean 11 months) after surgery. RESULTS: 13 male and 5 female patients aged between 45-77 years (mean 59.2±17.1 years) with 26 malignant and one most probable benign hepatic lesion were treated with intraoperative RFA. Io-CEUS detected 23 preoperatively unknown liver lesions leading to a change in therapy in 13/18 cases (72,2%). All 27 treated lesions showed an avascular area immediately after RFA. According to follow-up imaging results (1 month - 3 years after surgery, mean follow-up time 11 months), 2/18 patients had local recurrences, 8 patients had distant intrahepatic recurrences or extrahepatic recurrence, 8 patients remained tumor-free. Thereby, a success rate of CEUS guided RFA of 89% could be obtained concerning the targeted liver lesions. CONCLUSION: Modern intraoperative ultrasound using B-mode and Io-CEUS is a valuable tool for optimization of diagnostic and therapeutic intraoperative liver procedures and ablative therapies. [ABSTRACT FROM AUTHOR]

AIM: Comparison of different ultrasound elastography techniques for detection of changes after sclerotherapy within venous malformations. MATERIALANDMETHODS:In patients with venous malformations sonographywas executed at exactly the same position prior to and after ethanol-gel sclerotherapy. Both examinations included B-Mode, vascular sonography with Color-Coded Duplex Sonography, and additional sonography with different elastography techniques (strain, qualitative and quantitative Acoustic Radiation Force Impulse (ARFI) elastography) with a linear transducer (6-9 MHz). Qualitative elastograms were read in consensus and scored. Differences of elasticity scores were statistically analyzed, p-values < 0.05 were regarded significant. RESULTS: Elasticity scores of strain and qualitative ARFI elastography in 25 patients (21 females, averagely 24.4 years old) were comparable before treatment (p = 0.69). After therapy qualitative ARFI scores changed significantly compared to pre-treatment scores (p = 0.0017), whereas strain elastography scores revealed no significant changes (p = 0.13). Quantitative ARFI values obtained after sclerotherapy within the venous malformations were significantly higher compared to pretreatment values (p = 0.049), and significantly higher to values obtained in surrounding tissue (p = 0.030). Comparison of preand post-treatment ARFI values of the surrounding tissue was not significant (p = 0.67). CONCLUSION: Elasticity scores of qualitative ARFI elastography reliably detect ethanol-gel induced changes in venous malformations. Quantitative ARFI may be a tool for therapy planning, and for monitoring sclerotherapy outcome as well as the effect of sclerosing agents on malformation and surrounding tissue in patients with venous malformations. [ABSTRACT FROM AUTHOR]