Koshiro Ueda

Periostin links mechanical strain to inflammation in abdominal aortic aneurysm.

Aims Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation, which contributes to the pathological remodeling of the extracellular matrix. Although mechanical stress has been suggested to promote inflammation in AAA, the molecular mechanism remains uncertain. Periostin is a matricellular protein known to respond to mechanical strain. The aim of this study was to elucidate the role of periostin in mechanotransduction in the pathogenesis of AAA. Methods and Results We found significant increases in periostin protein levels in the walls of human AAA specimens. Tissue localization of periostin was associated with inflammatory cell infiltration and destruction of elastic fibers. We examined whether mechanical strain could stimulate periostin expression in cultured rat vascular smooth muscle cells. Cells subjected to 20% uniaxial cyclic strains showed significant increases in periostin protein expression, focal adhesion kinase (FAK) activation, and secretions of monocyte chemoattractant protein-1 (MCP-1) and the active form of matrix metalloproteinase (MMP)-2. These changes were largely abolished by a periostin-neutralizing antibody and by the FAK inhibitor, PF573228. Interestingly, inhibition of either periostin or FAK caused suppression of the other, indicating a positive feedback loop. In human AAA tissues in ex vivo culture, MCP-1 secretion was dramatically suppressed by PF573228. Moreover, in vivo, periaortic application of recombinant periostin in mice led to FAK activation and MCP-1 upregulation in the aortic walls, which resulted in marked cellular infiltration. Conclusion Our findings indicated that periostin plays an important role in mechanotransduction that maintains inflammation via FAK activation in AAA.

Subcutaneous Tissue Ultrasonography in Legs with Dependent Edema and Secondary Lymphedema

OBJECTIVES To elucidate the differences in subcutaneous ultrasound findings between dependent edema (DE) and secondary lower extremity lymphedema (LE). MATERIALS AND METHODS Twenty legs in 10 patients with DE and 54 legs in 35 patients with LE, who first visited our clinic between April 2009 and December 2012, were studied retrospectively. Subcutaneous echogenicity and echo-free space (EFS) were assessed at 8 points on the thigh and leg using an 8-12 MHz ultrasound transducer. RESULTS In DE, echogenicity was increased most in the lower leg, without a difference between the medial and lateral side. The EFS was most remarkable in the lower leg, and the lateral side was more severe. In the early stages of LE, echogenicity was similarly increased in the medial thigh and in the leg, while remarkable EFS was observed only in the lower leg. As clinical severity progressed, echogenicity increased in all parts of the lower extremity. EFS also increased in all parts of the leg, but the lower leg was still the most severe. CONCLUSION Echogenicity seemed to progress differently in DE and LE, but EFS progressed similarly and according to gravity. The current ultrasound findings may have added some diagnostic value in differentiating these conditions.

A study of increase in leg volume during complex physical therapy for leg lymphedema using subcutaneous tissue ultrasonography

OBJECTIVE The purpose of this study was to discuss the mode of increase in leg volume during complex physical therapy (CPT) for lymphedema using subcutaneous tissue ultrasonography. METHODS Thirty-eight patients (51 legs) with secondary lymphedema who were treated by CPT for longer than 2 years (3.0 ± 0.8 years) at our clinic were studied. The leg circumferences were measured at every visit. Subcutaneous tissue ultrasonography was performed at the initial and latest visits. RESULTS The overall change in leg volume was -284 ± 915 (range, -4588 to 1139) mL. Among them, the increase in leg volume was found in 18 legs; of those, 9 (1 in stage I, 7 in stage II, 1 in stage III) were adherent to hosiery use. In the legs whose average volume was decreased (group A, n = 33; mean, -821 [-4588 to -19] mL), the circumference had decreased in all the leg levels. However, in the legs whose average volumes had increased (group B, n = 18; mean, +449 [18-1139] mL), the circumference had increased in the thigh but remained unchanged or even decreased in the lower leg. In group B, subcutaneous thickness (SCT), subcutaneous echogenicity (SEG), and subcutaneous echo-free space (SEFS), assessed by ultrasonography, were found to have increased particularly in the lower medial thigh compared with those in group A (SCT change: group A, -1.5 ± 5.9 cm vs group B, 3.7 ± 5.4 cm [P < .05]; SEG grade change: group A, -0.3 ± 0.7 vs group B, 0.3 ± 0.7 [P < .05]; SEFS grade change: group A, -0.1 ± 0.7 vs group B, 0.4 ± 0.6 [P < .05]), whereas these remained unchanged or even decreased in the lower leg. CONCLUSIONS Increase in leg volume during CPT might not be caused simply by noncompliance to hosiery use and seemed closely related to the increase in thigh circumferences, particularly the lower thigh, in which SCT, SEG, and SEFS were increased.

Skin and Subcutaneous Tissue Strain in Legs with Lymphedema and Lipodermatosclerosis

We compared skin and subcutaneous tissue strains in legs with lymphedema (LE) of varying severity and legs with lipodermatosclerosis (LDS) using real-time tissue elastography. Strain was assessed at the inner thigh and calf in 62 legs with LE (International Society of Lymphology [ISL] stage 0: 16, stage I: 5, stage II: 28, late stage II: 7, stage III: 6) and 15 legs with LDS. In thighs and calves with LE, skin strain and subcutaneous tissue strain did not significantly differ between ISL stage 0, that is, asymptomatic legs, and other stages. However, strain values in calves with LDS were lower than values in calves with stage 0, II and late II LE. These results indicate that skin and subcutaneous tissue strains were not lower in legs with symptomatic LE than in asymptomatic legs until an advanced stage.

Possible Dual Role of Decorin in Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is characterized by chronic inflammation, which leads to pathological remodeling of the extracellular matrix. Decorin, a small leucine-rich repeat proteoglycan, has been suggested to regulate inflammation and stabilize the extracellular matrix. Therefore, the present study investigated the role of decorin in the pathogenesis of AAA. Decorin was localized in the aortic adventitia under normal conditions in both mice and humans. AAA was induced in mice using CaCl2 treatment. Initially, decorin protein levels decreased, but as AAA progressed decorin levels increased in all layers. Local administration of exogenous decorin prevented the development of CaCl2-induced AAA. However, decorin was highly expressed in the degenerative lesions of human AAA walls, and this expression positively correlated with matrix metalloproteinase (MMP)-9 expression. In cell culture experiments, the addition of decorin inhibited secretion of MMP-9 in vascular smooth muscle cells, but had the opposite effect in macrophages. The results suggest that decorin plays a dual role in AAA. Adventitial decorin in normal aorta may protect against the development of AAA, but macrophages expressing decorin in AAA walls may facilitate the progression of AAA by up-regulating MMP-9 secretion.

Adherence to and efficacy of different compression methods for treating chronic venous insufficiency in the elderly.

Objectives To investigate the adherence to and efficacy of different compression methods in elderly patients. Methods A retrospective review of compression therapy in 120 elderly patients (≥65 years) with chronic venous insufficiency was performed to study the initially preferred compression method, adherence to each method, and its efficacy. Results Initially, an oversize strong stocking (24%), an appropriate size moderate stocking (19%), and bandages (37%) were equally preferred. Adherence at 1 month was 69%, 96%, and 91%, respectively, and they reduced ankle circumferences in C3 patients by 1.8 ± 1.9 cm, 0.3 ± 1.7 cm, and 2.9 ± 1.7 cm, respectively. The improvement rates of C4 symptoms were 79%, 60%, and 91%, respectively. Only three patients (2%) preferred an appropriate size strong stocking. Conclusions In elderly patients, an appropriate size strong stocking was not preferred. The best adherence was achieved by using a moderate stocking, while the best efficacy was achieved by using bandages.

Study on different bandages and application techniques for achieving stiffer compression.

Objectives The objective of this study was to investigate the relationship between interface pressure and stiffness of compression achieved by various combinations of bandages and application techniques. Method There were eight healthy volunteers. One roll (4.5 m) of four types of bandages with different extensibilities (0, 90, 108 and 218%) was applied to the leg in single-layer bandage fashion with eight random tensions. Then, the leg was wrapped with one to eight rolls in multi-layer bandage fashion. Results Each combination of bandage and application technique displayed an indigenous linear interface pressure-static stiffness index relationship. With single-layer bandage, lower extensibility was associated with higher static stiffness index at a given interface pressure. With multi-layer bandage, the static stiffness index at a given interface pressure was independent of the bandage type. Conclusion The stiffness at a given interface pressure was affected by the extensibility with single-layer bandage but not with multi-layer bandage.

Focal Adhesion Kinase Promotes the Progression of Aortic Aneurysm by Modulating Macrophage Behavior.

Objective— Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease that is associated with persistent inflammation and extracellular matrix degradation. The molecular mechanisms underlying the macrophage-mediated progression of AAA remain largely unclear. Approach and Results— We show that focal adhesion kinase (FAK) expression and activity are enhanced in macrophages that are recruited to AAA tissue. FAK potentiates tumor necrosis factor-&agr;–induced secretion of matrix-degrading enzymes and chemokines by cultured macrophages. FAK also promotes macrophage chemotaxis. In mice, the administration of a FAK inhibitor that tempers local macrophage accumulation markedly suppresses the development and progression of chemically induced AAA. Conclusions— FAK plays a key role in macrophage behavior, which underlies the chronic progression of AAA. These findings provide insights into AAA progression and identify FAK as a novel therapeutic target.

Immediate Changes to Skin and Subcutaneous Tissue Strains Following Manual Lymph Drainage in Legs with Lymphedema.

OBJECTIVES To study the immediate impact of manual lymph drainage (MLD) on skin and subcutaneous tissue strains in legs with lymphedema using free-hand real-time tissue elastography (RTE). METHODS Skin and subcutaneous tissue strain measurements were taken at the middle of the inner thigh and calf by RTE in 20 legs with lymphedema of 18 patients (stage II: 11, late stage II: 7, stage III: 2) and in 70 legs of 35 normal subjects. In patients with lymphedema, the same measurements were repeated immediately following MLD. RESULTS Significant negative correlations were found between pre-MLD strains and the MLD-induced changes in thigh and calf skin strains (thigh skin: p <0.01, calf skin: p = 0.05), but not in subcutaneous tissue strains. Pre-MLD intercepts of these regression lines were closer to normal values as compared to mean pre-MLD values (normal thigh skin: 0.54% ± 0.30%, calf skin: 0.25% ± 0.18%, Pre-MLD thigh skin: 0.39% ± 0.20%, calf skin: 0.17% ± 0.12%, Pre-MLD intercept of thigh skin: 0.48%, Pre-MLD intercept of calf skin: 0.31%). CONCLUSIONS It appears that MLD did not simply soften the skin, but rather normalized it in terms of strain. However, this was not confirmed in the subcutaneous tissue.

A novel arm sleeve for upper extremity lymphedema: a pilot study.

OBJECTIVE To investigate the safety and efficacy of a novel arm sleeve composed of a conventional arm sleeve extending to a wider area of the body. MATERIALS AND METHODS Five subjects with post-mastectomy upper extremity lymphedema, who had already been using their own arm sleeve, used a brand-new conventional arm sleeve for 2 weeks, followed by a novel arm sleeve for 2 weeks. The adverse events, arm-related symptoms, interface pressures, and subcutaneous fluid distributions observed by magnetic resonance imaging (MRI) were assessed. RESULTS The use of the novel arm sleeve resulted in a graduated compression extending to the shoulder (forearm, 21.8 ± 3.7 mmHg; upper arm, 15.2 ± 3.3 mmHg; shoulder, 8.8 ± 3.1 mmHg). By eliminating the wring seen in the conventional arm sleeve, the disturbed proximal diffusion of the subcutaneous fluid and venous occlusion were successfully avoided, as confirmed by MRI. No adverse event or worsening of arm-related symptoms was reported. CONCLUSION The novel arm sleeve seemed to provide graduated compression to a wider area, allowing improved subcutaneous fluid and venous drainage without any adverse events. Therefore, the novel arm sleeve may be recommended as a compression therapy option for upper extremity lymphedema.