Angiopoietin-Tie signaling in kidney diseases: an updated review.

Angiopoietins (Angs) are a family of vascular growth factors that share multiple cellular functions related to cell survival, proliferation, and migration. Angs play physiological and pathological roles through the Tie tyrosine kinase receptors. The Ang-Tie signaling pathway participates in the developmental and tumor-induced angiogenesis and is also involved in many disease settings, such as vascular diseases, systemic inflammation, and cancers. Since Angs are widely expressed in the kidney, an enormous amount of research focuses on their roles in the kidney. In this review, we describe the biological functions of the Ang-Tie signaling pathway and summarize their roles in kidney development and maturation, acute and chronic kidney diseases, diabetic nephropathy, lupus nephropathy, hemolytic uremic syndrome, end-stage renal diseases, and renal cell carcinoma. Understanding the molecular mechanisms of Ang-Tie signaling may reveal potential therapeutic targets for preventing or alleviating kidney diseases.

Safe extensive tumescent liposuction with segmental infiltration of lower concentration lidocaine under monitored anesthesia care.

Tumescent anesthesia makes it feasible to perform liposuction in an office setting. There are often patients who desire extensive liposuction on approximately 30% of total body surface area, which means the lidocaine total dose might be over the dosing recommendation. So the segmental infiltration is applied, although the concentration of lidocaine in tumescent fluid is gradually reduced to 0.0252%. Moreover, supplemental intravenous (IV) sedation using monitored anesthesia care is usually applied concurrently to help alleviate discomfort and pain of the patients during tumescent anesthetic infusion and fat extraction which in turn increases the risks of potential lidocaine toxicity due to possible drug interactions. This study was to demonstrate the safety of segmental infiltration of tumescent fluid with lower lidocaine concentration combined with IV sedation in extensive liposuction and determine whether the risk of lidocaine toxicity is increased in this protocol. Ten female patients who requested the extensive liposuction participated in the study. The targeted areas were divided into 2 segments and treated in turn in 1 session. Lidocaine (1600 mg) was infiltrated into the first segment, and approximately 928 mg lidocaine was subsequently infiltrated after accomplishment of the first segment operation. Serum levels of lidocaine were taken every 4 hours during the first 24 hours after the second infiltration. The average time of the procedure is 222 (33) minutes. The dose and total amount of lidocaine injected are 40.7 (5.8) mg/kg and 2528.2 (155.2) mg, respectively. The total volume of the infusates and aspirates are 9918.1 (494) and 6325 (1461.6) mL, respectively, the ratio of total infusates to total aspirates is 1.66 (0.45). The total aspirated fat and fluids are 3280 (1051.8) and 3045 (824.1) mL, respectively. The peak lidocaine levels [2.18 (0.63) µg/mL] occurred after 12 to 20 hours [16.4 (2.27) hours]. No significant correlation between dose per kilogram body weight or total dose of lidocaine infiltrated and its peak levels or time existed. The extensive liposuction covering the 30% total body surface areas was well tolerated by the patients under tumescent anesthesia in combination with the supplemental IV sedation. Our previous study on the fluid management has demonstrated the risk of hypovolemia or fluid overload is very low with this technique, although the patients who received only maintenance fluid (500 mL) in the operating room and could discharge and resume oral intake after 6 hours of recovery room stay. The adequate anesthesia support is available in our office-based setting with adequate recovery facilities in place. It has a high margin of safety, without increasing of lidocaine toxicity or adverse cardiopulmonary sequelae while using a segmental tumescent infiltration with lower concentration of lidocaine.

Angiopoietin-2 promotes inflammatory lymphangiogenesis and its effect can be blocked by the specific inhibitor L1-10.

Angiopoietin (Ang)-2, a ligand of the receptor tyrosine kinase Tie2, is known to be involved in the regulation of embryonic lymphangiogenesis. However, the role of Ang-2 in postnatal pathological lymphangiogenesis, such as inflammation, is largely unknown. We used a combination of imaging, molecular, and cellular approaches to investigate whether Ang-2 is involved in inflammatory lymphangiogenesis. We observed strong and continuous expression of Ang-2 on newly generated lymphatic vessels for 2 wk in sutured corneas of BALB/c mice. This expression was concurrent with an increased number of lymphatic vessels. TNF-α expression also increased, with peak TNF-α expression occurring before peak Ang-2 expression was reached. In vitro experiments showed that TNF-α stimulates Ang-2 and Tie2 and ICAM-1 expression on human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BECs). Ang-2 alone did not affect the biological behavior of LECs, whereas Ang-2 combined with TNF-α significantly promoted the proliferation of LECs but not BECs. In mouse models, blockade of Ang-2 with L1-10, an Ang-2-specific inhibitor, significantly inhibited lymphangiogenesis but promoted angiogenesis. These results clearly indicate that Ang-2 acts as a crucial regulator of inflammatory lymphangiogenesis by sensitizing the lymphatic vasculature to inflammatory stimuli, thereby directly promoting lymphangiogenesis. The involvement of Ang-2 in inflammatory lymphangiogenesis provides a strong rationale for the exploitation of anti-Ang-2 treatment in the prevention and treatment of tumor metastasis and transplant rejection.

[Treatment of chronic extremity lymphedema with manual lymph drainage].

OBJECTIVE: To evaluate the effect of manual lymph drainage on chronic extremity lymphedema. METHODS: Fifty patients with chronic lymphedema of extremity were treated with manual lymph drainage (MLD) complex decongestion therapy. Among them, 29 had primary lymphedema, 21 had secondary lymphedema. 42 had lymphedema of lower extremity and 8 had lymphedema of upper limb. The result of treatment was evaluated with measurement of circumference of extremities and edema fluid in tissue with Multiple-frequency bioelectrical impedance analysis. RESULTS: After 1-2 treatment courses, all 50 patients showed significant decrease of circumference of lymphomatous limbs (P < 0.05) and remarkable reduction of accumulated edema fluid in tissue (P < 0. 05). There was highly correlation between the decrease of limb circumference and edema fluid in tissue (r(s) = 0.774, P < 0.01). CONCLUSIONS: MLD complex decongestion therapy is effective for the treatment of chronic lymphedema of extremity.

Reconstruction of lymph vessel by lymphatic endothelial cells combined with polyglycolic acid scaffolds: a pilot study.

Restoration of lymphatic drainage using lymph vessels or tissue grafting is becoming an efficient method for alleviating obstructive lymphedema. However, the lack of ideal lymphatic grafts is the key problem that limits the application of lymphatic transplantation, but now that may be resolved with tissue-engineered lymph vessels. In this study, the feasibility of reconstructing lymph vessels was explored using lymphatic endothelial cells (LECs) combined with polyglycolic acid (PGA) scaffolds. The highly purified human dermal LECs can be isolated from human dermis by immunomagnetic bead sorting and multiplied in culture. The viability and growth potential of subcultured LECs make it possible to obtain large amount of cells in vitro. Light and scanning electron microscopy (SEM) showed that the prefabricated PGA scaffolds, with three-dimensional structure, can support cell adhesion, growth and spreading. The constructs formed with LECs combined with PGA scaffolds were cultured in vitro for 10 days and then implanted subcutaneously into nude mice. Six weeks after implantation, the portions of implanted tubules were harvested. Gross and histological observation demonstrated that the tubular structure still remained in the experimental groups but not in the control groups. Immunohistochemical staining and RT-PCR assay of the implanted vessels revealed positive staining in experimental groups for the lymphatic specific markers Podoplanin, VEGFR-3 and LYVE-1. The results indicate that LECs can serve as seed cells and be successfully combined with PGA scaffolds, and the tissue-engineered tubular structure using implanted LECs-PGA compounds showed preliminary characteristics of lymph vessels. A gap between the nearly normal or functional lymph vessel still exists as we have only the endothelial cell-lined duct, but this study demonstrates that it is feasible to construct tissue-engineered lymph vessels using LECs combined with a biodegradable material.

[Diagnosis of peripheral lymph circulation disorders with contrast MR lymphangiography].

OBJECTIVE: To evaluate anatomical and functional images of contrast MR lymphangiography in the diagnosis of limb lymphatic circulation disorders. METHODS: 30 patients with limb lymphedema were enrolled in the study. There were 27 patients of primary lymphedema and 3 of secondary lymphedema. Contrast enhanced lymphangiography was performed with 3.0 T MR Unit after intracutaneous injection of gadobenate dimeglumine into the interdigital webs of the dorsal foot and hand. The kinetics of enhanced lymph flow within the lymphatics were calculated using the formula: Speed (cm) = total length of visualized lymph vessel (cm)/ inspection time (minutes) and by comparing dynamic nodal enhancement and time-signal intensity curves between edematous and contralateral limbs. Morphological abnormalities of the lymphatic system were also evaluated. RESULTS: Following injection of the contrast agent enhanced lymphatic channels were consistently visualized in all clinical lymphedematous limbs and five contralateral limbs of unilateral lymphedema cases. The speed of enhanced flow within the lymphatics of lymphedematous limbs ranged from 0.30 to 1.48 cm/min. The contrast enhancement in inguinal nodes of edematous limbs was significantly lower than that of contralateral limbs (P < 0.01). Dynamic measurement of contrast enhancement showed a remarkable lowering of peak time (P < 0.01) and peak enhancement (P < 0.01) and a delay in outflow in inguinal nodes of affected limbs compared with that of control limbs. Post-contrast MR imaging also depicted varied distribution patterns of lymphatics and abnormal lymph flow pathways within lymph nodes in the limbs with lymphatic circulation disorders. CONCLUSIONS: Contrast MR lymphangiography with gadobenate dimeglumine was able to visualize the precise anatomy of lymphatic vessels and lymph nodes in lymphedematous limbs. It also provided comprehensive information about the functional status of lymph flow transportation in lymphatics and lymph nodes.

Simultaneous determination of herbicide mefenacet and its metabolites residues in river water by solid phase extraction and rapid resolution liquid chromatography-mass spectrometry with pre-column derivatization.

A procedure based on solid phase extraction (SPE) has been developed for the simultaneous pre-concentration of herbicide mefenacet (MN) and its three photolysis degradation products. Three metabolites studied were hydroxylbenzothiazole (HBT), N-methylaniline (N-MA) and 2-benzothiazoloxyacetic acid (2-BAA). A trimethylsilylation derivatization method was applied for the analysis of HBT and 2-BAA which were derivatized to be corresponding derivatives D-1 and D-2, respectively, and a rapid resolution liquid chromatography-electrospray ionization mass spectrometry (RRLC-ESI-MS) system was used for the separation, identification and quantification of these four analytes. In the SPE pre-concentration step, three types of cartridges and four kinds of eluents were investigated. The mean recoveries of these four analytes were between 78.6% and 101.2% and relative standard deviations were between 3.2% and 9.2%. The limits of detection (LODs) obtained were 0.02 ng l(-1) for MN and N-MA and 0.1 ng l(-1) for HBT and 2-BAA which were less than the maximum residue limits (MRLs) in drinking water established by European legislation (0.1 microg l(-1)). The proposed method was applied to evaluate the presence and evolution with time of herbicide mefenacet and its degradation products in samples of Songhuajiang River of Heilongjiang province, China. The analyses, conducted from April to July of 2008, pointed to the presence of MN, 2-BAA, HBT and N-MA at maximum levels 1.0, 0.08, 0.1 and 0.3 microg l(-1).

Anatomic and functional evaluation of the lymphatics and lymph nodes in diagnosis of lymphatic circulation disorders with contrast magnetic resonance lymphangiography.

OBJECTIVES: Owing to its structural and anatomic characteristics, imaging of the lymphatic system has been difficult. The conventional diagnostic method of radionuclide-based imaging has the disadvantage of poor resolution. Recent work has shown that magnetic resonance imaging (MRI) can depict lymphatic channels in patients with lymphedema. This study evaluated the anatomic and functional images of contrast MR lymphangiography in the diagnosis of limb lymphatic circulation disorders. METHODS: The study enrolled 27 patients with primary lymphedema. Four patients had bilateral disease, and 23 had unilateral disease. Contrast-enhanced lymphangiography was performed with a 3.0-T MR unit after the intracutaneous injection of gadobenate dimeglumine into the interdigital webs of the dorsal foot. The kinetics of enhanced lymph flow within the lymphatic system were calculated using the formula [speed in cm = total length of visualized lymph vessel in cm/inspection time in minutes] and by comparing dynamic nodal enhancement and time-signal intensity curves between edematous and contralateral limbs. Morphologic abnormalities of the lymphatic system were also evaluated. RESULTS: Examination of the MRIs after injection of the contrast agent showed enhanced lymphatic channels consistently visualized in all clinical lymphedematous limbs and in five contralateral limbs of unilateral lymphedema patients. The speed of flow within the lymphatics of lymphedematous limbs was 0.3 to 1.48 cm/min. Contrast enhancement in inguinal nodes of edematous limbs was significantly less than that of contralateral limbs (P < .01). Dynamic measurement of contrast enhancement showed a remarkable lowering of peak time (P < .01) and peak enhancement (P < .01), and a delay in outflow in inguinal nodes of affected limbs compared with that of control limbs. Postcontrast MRI also depicted varied distribution patterns of lymphatics and abnormal lymph flow pathways within lymph nodes in the limbs with lymphatic circulation disorders. CONCLUSION: Contrast MR lymphangiography with gadobenate dimeglumine is capable of visualizing the precise anatomy of lymphatic vessels and lymph nodes in lymphedematous limbs. It also provides information concerning the functional status of lymph flow transport in the lymphatic vessels and lymph nodes of these limbs.

[Experimental studies of VEGF-C gene for the treatment of chronic obstructive lymphedema in mouse tail model].

OBJECTIVE: To study the therapeutic effect of vascular endothelial growth factor C (VEGF-C) gene for chronic obstructive lymphedema in mouse tail model which may provide a new treatment for lymphedema. METHODS: RT-PCR and immunoabsorption were applied to detect VEGF-C gene expression in fibroblasts and secretion of VEGF-C protein in COS7 cells respectively after pCDNA3.1 (+) VEGF-C transfection. A mouse tail model of chronic obstructive lymphedema was created. Then the pcDNA3.1-VEGF-C plasmid was injected into the tail. The effect of modulating lymphangiogenesis was observed. RESULTS: Compared with control group, overexpression of VEGF-C enhanced lymphangiogenesis in vivo and mouse tail skin suffering chronic obstructive lymphedema was improved by VEGF-C gene significantly. CONCLUSIONS: VEGF-C can improve the lymphedema through enhancing lymphangiogenesis.

Determination of hydroxyl radicals in TiO2/Ti photoelectrocatalytic oxidation system using Fe(phen)3(2+) spectrophotometry.

A new method of determining the cumulate concentration of hydroxyl radicals in the TiO2/Ti photoelectrocatalytic (PEC) oxidation system was established by o-phenanthroline-Fe(II)(Fe(phen)3(2+)) spectrophotometry and using anion exchange membrane. Fe (phen)3(2+) can be oxidized to o-phenanthroline-Fe(III)(Fe(phen)3(3+)) by strong oxidization of hydroxyl radicals(*OH). Then the cumulate concentration of hydroxyl radicals can be calculated through determining the change of the Fe(phen)3(3+) absorbency at 509 nm. In addition, the research results showed the production rate of hydroxyl radicals was affected obviously by pH of solution, the cumulate concentration of hydroxyl radicals was the largest at nearby the initial pH 6.3 (isoelectric point), and the change direction of pH after illumination tended to nearby isoelectric point.