Regulation of lymphatic capillary regeneration by interstitial flow in skin

Decreased interstitial flow (IF) in secondary lymphedema is coincident with poor physiological lymphatic regeneration. However, both the existence and direction of causality between IF and lymphangiogenesis remain unclear. This is primarily because the role of IF and its importance relative to the action of the prolymphangiogenic growth factor vascular endothelial growth factor (VEGF)-C (which signals primarily through its receptor VEGFR-3) are poorly understood. To clarify this, we explored the cooperative roles of VEGFR-3 and IF in a mouse model of lymphangiogenesis in regenerating skin. Specifically, a region of lymphangiogenesis was created by substituting a portion of mouse tail skin with a collagen gel within which lymphatic capillaries completely regenerate over a period of 60 days. The relative importance of IF and VEGF-C signaling were evaluated by either inhibiting VEGFR-3 signaling with antagonistic antibodies or by reducing IF. In some cases, VEGF-C signaling was then increased with exogenous protein. To clarify the role of IF, the distribution of endogenous matrix metalloproteinases (MMPs) and VEGF-C within the regenerating region was determined. It was found that inhibition of either VEGFR-3 or IF suppressed endogenous lymphangiogenesis. Reduction of IF was found to decrease lymphatic migration and transport of endogenous MMP and VEGF-C through the regenerating region. Therapeutic VEGF-C administration restored lymphangiogenesis following inhibition of VEGFR-3 but did not increase lymphangiogenesis following inhibition of IF. These results identify IF as an important regulator of the pro-lymphangiogenic action of VEGF-C

Signifying “students”, “teachers” and “mathematics”: a reading of a special issue

This paper examines a Special Issue of Educational Studies in Mathematics comprising research reports centred on Peircian semiotics in mathematics education, written by some of the major authors in the area. The paper is targeted at inspecting how subjectivity is understood, or implied, in those reports. It seeks to delineate how the conceptions of subjectivity suggested are defined as a result of their being a function of the domain within which the authors reflexively situate themselves. The paper first considers how such understandings shape concepts of mathematics, students and teachers. It then explores how the research domain is understood by the authors as suggested through their implied positioning in relation to teachers, teacher educators, researchers and other potential readers

The interstitium in cardiac repair: role of the immune-stromal cell interplay

Cardiac regeneration, that is, restoration of the original structure and function in a damaged heart, differs from tissue repair, in which collagen deposition and scar formation often lead to functional impairment. In both scenarios, the early-onset inflammatory response is essential to clear damaged cardiac cells and initiate organ repair, but the quality and extent of the immune response vary. Immune cells embedded in the damaged heart tissue sense and modulate inflammation through a dynamic interplay with stromal cells in the cardiac interstitium, which either leads to recapitulation of cardiac morphology by rebuilding functional scaffolds to support muscle regrowth in regenerative organisms or fails to resolve the inflammatory response and produces fibrotic scar tissue in adult mammals. Current investigation into the mechanistic basis of homeostasis and restoration of cardiac function has increasingly shifted focus away from stem cell-mediated cardiac repair towards a dynamic interplay of cells composing the less-studied interstitial compartment of the heart, offering unexpected insights into the immunoregulatory functions of cardiac interstitial components and the complex network of cell interactions that must be considered for clinical intervention in heart diseases

The resolution of lymphedema by interstitial flow in the mouse tail skin

Lymphangiogenesis is considered a promising approach for increasing fluid drainage during secondary lymphedema. However, organization of lymphatics into functional capillaries may be dependent upon interstitial flow (IF). The present study was undertaken to determine the importance of lymphangiogenesis for lymphedema resolution. We created a lymphatic obstruction that produces lymphedema in mouse tail skin. The relatively scar-free skin regeneration that occurred across the obstruction allowed the progression of lymphangiogenesis to be observed and compared with the evolution of lymphedema. The role of vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3 signaling in lymphedema resolution was investigated by exogenous administration of VEGF-C or neutralizing antibodies against VEGFR-3. VEGF-C protein improved lymphedema at 15 days [reducing dermal thickness from 742 ± 105 to 559 ± 141 μm with 95% confidence intervals (CIs), P \u3c 0.05] without increasing lymphatic capillary coverage (11.6 ± 6.4% following VEGF-C treatment relative to 9.6 ± 6.2% with 95% CIs, P \u3e 0.50). Blocking VEGFR-3 signaling did not inhibit lymphedema resolution at 25 days (dermal thickness of 462 ± 127 μm following VEGFR-3 inhibition relative to 502 ± 87 μm with 95% CIs) or inhibit IF, although VEGFR-3 blocking prevented lymphangiogenesis (reducing lymphatic coverage to 0.2 ± 0.7% relative to 8.7 ± 7.3% with 95% CIs, P \u3c 0.005). A second mouse tail lymphedema model was employed to investigate the ability of VEGF-C to increase fluid drainage across a scar. We found that neither neutralization of VEGFR-3 nor administration of VEGF-C affected the course of skin swelling over 25 days. These findings suggest that resolution of lymphedema in the mouse tail skin may be more dependent upon IF and regeneration of the extracellular matrix across the obstruction than lymphatic capillary regeneration. Copyright © 2008 the American Physiological Society

Lymphangiogenesis-independent resolution of experimental edema

Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis, and excess VEGF-C has been shown to be ameliorative for edema produced by lymphatic obstruction in experimental models. However, it has recently been shown that edema can resolve in the mouse tail even in the complete absence of capillary lymphangiogenesis when distal lymph fluid crosses the regenerating wound site interstitially. This finding has raised questions about the action of VEGF-C/VEGF receptor (VEGFR) signaling during the resolution of experimental edema. Here, the roles of VEGFR-2 and VEGFR-3 signaling in edema resolution were explored. It was found that edema resolved following neutralization of either VEGFR-2 or VEGFR-3 in the mouse tail skin, which inhibited lymphangiogenesis. Neutralization of either VEGFR-2 or VEGFR-3 reduced angiogenesis at the site of obstruction at day 10 (9.2 ± 1.2% and 11.5 ± 1.0% blood capillary coverage, respectively) relative to controls (14.3 ± 1.5% blood capillary coverage). Combined VEGFR-2/-3 neutralization more strongly inhibited angiogenesis (6.9 ± 1.5% blood capillary coverage), leading to a reduced wound repair of the lymphatic obstruction and extended edema in the tail skin. In contrast, improved tissue repair of the obstruction site increased edema resolution. Macrophages in the swollen tissue were excluded as contributing factors in the VEGFR-dependent extended edema. These results support a role for VEGFR-2/-3-combined signaling in the resolution of experimental edema that is lymphangiogenesis independent

High Plasma Levels of Soluble Lectin‐like Oxidized Low‐Density Lipoprotein Receptor‐1 Are Associated With Inflammation and Cardiometabolic Risk Profiles in Pediatric Overweight and Obesity

Background Lectin‐like oxidized low‐density lipoprotein (ox‐LDL) receptor‐1 is a scavenger receptor for oxidized low‐density lipoprotein. In adults, higher soluble lectin‐like ox‐LDL receptor‐1 (sLOX‐1) levels are associated with cardiovascular disease, type 2 diabetes, and obesity, but a similar link in pediatric overweight/obesity remains uncertain. Methods and Results Analyses were based on the cross‐sectional HOLBAEK Study, including 4‐ to 19‐year‐olds from an obesity clinic group with body mass index >90th percentile (n=1815) and from a population‐based group (n=2039). Fasting plasma levels of sLOX‐1 and inflammatory markers were quantified, cardiometabolic risk profiles were assessed, and linear and logistic regression analyses were performed. Pubertal/postpubertal children and adolescents from the obesity clinic group exhibited higher sLOX‐1 levels compared with the population (P<0.001). sLOX‐1 positively associated with proinflammatory cytokines, matrix metalloproteinases, body mass index SD score, waist SD score, body fat %, plasma alanine aminotransferase, serum high‐sensitivity C‐reactive protein, plasma low‐density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure SD score, and inversely associated with plasma high‐density lipoprotein cholesterol (all P<0.05). sLOX‐1 positively associated with high alanine aminotransferase (odds ratio [OR], 1.16, P=4.1 E‐04), insulin resistance (OR, 1.16, P=8.6 E‐04), dyslipidemia (OR, 1.25, P=1.8 E‐07), and hypertension (OR, 1.12, P=0.02). Conclusions sLOX‐1 levels were elevated during and after puberty in children and adolescents with overweight/obesity compared with population‐based peers and associated with inflammatory markers and worsened cardiometabolic risk profiles. sLOX‐1 may serve as an early marker of cardiometabolic risk and inflammation in pediatric overweight/obesity. Registration The HOLBAEK Study, formerly known as The Danish Childhood Obesity Biobank, ClinicalTrials.gov identifier number NCT00928473, https://clinicaltrials.gov/ct2/show/NCT00928473 (registered June 2009)

Multicenter Analysis of Endovascular Aortic Arch In Situ Stent-Graft Fenestrations for Aortic Arch Pathologies

Background: In situ fenestration of aortic stent grafts for treatment of aortic arch aneurysms is a new option for endovascular aortic arch repair. So far, only few reports have shown perioperative and short-term results of in situ fenestrations for aortic arch diseases. We present the multicenter experience with the aortic arch in situ fenestration technique documented in the AARCHIF registry for treatment of aortic arch aneurysms or localized type A aortic dissections and analyzed perioperative outcome and midterm follow-up. Methods: Patients with aortic arch pathologies treated by aortic arch in situ fenestration with proximal stent graft landing in aortic arch Ishimura zones 0 and 1 were included in the registry. Stent-graft in situ fenestrations were created using needles or radiofrequency or laser catheters and completed by implantation of covered connecting stent grafts. Single in situ fenestrations for the left subclavian artery (LSA) were excluded. Results: Between 06/2009 and 03/2017, twenty-five patients were treated by in situ stent-graft fenestrations for aortic arch pathologies at 9 institutions in 7 different countries, 3 of them as bailout procedures for stent-graft malplacement. In situ fenestrations were performed for the bra-chiocephalic trunk (n = 20), the left common carotid artery (n = 21) and the LSA (n = 9). Technical success for intended in situ fenestrations was 94.0% (47/50), with additional supraaortic bypass procedures performed in 14 patients. Perioperative mortality occurred in 1 (4.0%) patient, treated as a bailout procedure and 3 (12.0%) perioperative strokes were observed. One proximal aortic stent-graft nonalignment and 4 type III endoleaks, 2 early and 2 late, required reeintervention. During follow-up (1-118 months), the diameter of aortic arch aneurysms decreased from 61.5 +/- 4.1 mm to 48.4 +/- 3.2 mm (P = 0.02) and, so far, 6 patients died from diseases unrelated to their aortic arch pathologies with a mean survival time of 79.5 months and 3 endovascular reinterventions for distal aortic expansion were performed. Cerebrovascular event (n = 4) was the most relevant prognostic factor for mortality during midterm follow-up (P = 0.003). Conclusions: The aortic arch in situ fenestration technique for endovascular aortic arch repair seems to be valuable treatment option for selected patients, although initial consideration of other treatment options is mandatory. Data about long-term durability are required