Increased MFG-E8 at neuromuscular junctions is an exacerbating factor for sarcopenia-associated denervation.

Sarcopenia is an important health problem associated with adverse outcomes. Although the etiology of sarcopenia remains poorly understood, factors apart from muscle fibers, including humoral factors, might be involved. Here, we used cytokine antibody arrays to identify humoral factors involved in sarcopenia and found a significant increase in levels of milk fat globule epidermal growth factor 8 (MFG-E8) in skeletal muscle of aged mice, compared with young mice. We found that the increase in MFG-E8 protein at arterial walls and neuromuscular junctions (NMJs) in muscles of aged mice. High levels of MFG-E8 at NMJs and an age-related increase in arterial MFG-E8 have also been identified in human skeletal muscle. In NMJs, MFG-E8 is localized on the surface of terminal Schwann cells, which are important accessory cells for the maintenance of NMJs. We found that increased MFG-E8 at NMJs precedes age-related denervation and is more prominent in sarcopenia-susceptible fast-twitch than in sarcopenia-resistant slow-twitch muscle. Comparison between fast and slow muscles further revealed that arterial MFG-E8 can be uncoupled from sarcopenic phenotype. A genetic deficiency in MFG-E8 attenuated age-related denervation of NMJs and muscle weakness, providing evidence of a pathogenic role of increased MFG-E8. Thus, our study revealed a mechanism by which increased MFG-E8 at NMJs leads to age-related NMJ degeneration and suggests that targeting MFG-E8 could be a promising therapeutic approach to prevent sarcopenia.

Liver fibrosis-induced muscle atrophy is mediated by elevated levels of circulating TNFα.

Liver cirrhosis is a critical health problem associated with several complications, including skeletal muscle atrophy, which adversely affects the clinical outcome of patients independent of their liver functions. However, the precise mechanism underlying liver cirrhosis-induced muscle atrophy has not been elucidated. Here we show that serum factor induced by liver fibrosis leads to skeletal muscle atrophy. Using bile duct ligation (BDL) model of liver injury, we induced liver fibrosis in mice and observed subsequent muscle atrophy and weakness. We developed culture system of human primary myotubes that enables an evaluation of the effects of soluble factors on muscle atrophy and found that serum from BDL mice contains atrophy-inducing factors. This atrophy-inducing effect of BDL mouse serum was mitigated upon inhibition of TNFα signalling but not inhibition of myostatin/activin signalling. The BDL mice exhibited significantly up-regulated serum levels of TNFα when compared with the control mice. Furthermore, the mRNA expression levels of Tnf were markedly up-regulated in the fibrotic liver but not in the skeletal muscles of BDL mice. The gene expression analysis of isolated nuclei revealed that Tnf is exclusively expressed in the non-fibrogenic diploid cell population of the fibrotic liver. These findings reveal the mechanism through which circulating TNFα produced in the damaged liver mediates skeletal muscle atrophy. Additionally, this study demonstrated the importance of inter-organ communication that underlies the pathogenesis of liver cirrhosis.

Mesenchymal Bmp3b expression maintains skeletal muscle integrity and decreases in age-related sarcopenia.

Age-related sarcopenia constitutes an important health problem associated with adverse outcomes. Sarcopenia is closely associated with fat infiltration in muscle, which is attributable to interstitial mesenchymal progenitors. Mesenchymal progenitors are nonmyogenic in nature but are required for homeostatic muscle maintenance. However, the underlying mechanism of mesenchymal progenitor-dependent muscle maintenance is not clear, nor is the precise role of mesenchymal progenitors in sarcopenia. Here, we show that mice genetically engineered to specifically deplete mesenchymal progenitors exhibited phenotypes markedly similar to sarcopenia, including muscle weakness, myofiber atrophy, alterations of fiber types, and denervation at neuromuscular junctions. Through searching for genes responsible for mesenchymal progenitor-dependent muscle maintenance, we found that Bmp3b is specifically expressed in mesenchymal progenitors, whereas its expression level is significantly decreased during aging or adipogenic differentiation. The functional importance of BMP3B in maintaining myofiber mass as well as muscle-nerve interaction was demonstrated using knockout mice and cultured cells treated with BMP3B. Furthermore, the administration of recombinant BMP3B in aged mice reversed their sarcopenic phenotypes. These results reveal previously unrecognized mechanisms by which the mesenchymal progenitors ensure muscle integrity and suggest that age-related changes in mesenchymal progenitors have a considerable impact on the development of sarcopenia.

Popliteal artery entrapment by an enlarged sesamoid bone.

A 64-year-old woman came to our hospital because of intermittent claudication of her left leg. She had undergone meniscectomy of the left knee in her 30s. The ankle-brachial pressure index of the left leg was 0.70. Imaging examinations showed occlusion of the popliteal artery compressed by an enlarged sesamoid bone with osteophytes. No anatomic abnormalities of vessels and muscles were seen. A particular type of popliteal entrapment syndrome was diagnosed. After resection of the sesamoid bone, thromboendarterectomy and patch plasty were performed. After the operation, the claudication was improved, and the ankle-brachial pressure index of the left leg increased to 0.91.

Introduction of arteriovenous grafts with graft insertion anastomosis for hemodialysis access.

OBJECTIVE: An arteriovenous bridging graft is a viable option for patients with compromised arteries or veins because of advanced age or diabetes. Arteriovenous graft with graft insertion anastomosis (AVGI) is the novel technique for graft-vein anastomosis where the prosthesis is inserted into the vein, and the anastomosis is performed on the surface of the prosthesis. This study assessed the short-term and long-term results of AVGI to clarify the efficacy of this technique. METHODS: Between 2010 and 2015, AVGI was performed in graft-vein anastomosis of prosthetic forearm loop access. Characteristics and level of complications were assessed. To evaluate the long-term results, functional graft patency and frequency of percutaneous transluminal angioplasty were examined. RESULTS: The study comprised 58 patients. There were no deaths related to the surgery. The time of hemostasis after AVGI was recorded at 0 seconds because no bleeding from the suture holes was seen. At 1, 2, and 3 years, primary patency were 45.1% ± 7.5%, 23.1% ± 7.5%, and 23.1% ± 7.5%, respectively, and assisted primary patency rates were 59.4% ± 7.2%, 50.8% ± 7.6%, and 50.8% ± 7.6%, respectively. Secondary patency rates at 4 and 5 years were 100% ± 0% and 94.1% ± 5.7%, respectively. The frequency of percutaneous balloon angioplasty to maintain the patency was 1.61 ± 0.53 times per year. Graft infection occurred in four patients (6.9%). CONCLUSIONS: AVGI is an advantageous technique for graft vein anastomosis in an arteriovenous bridging graft in both the short-term and long-term.

Intermittent claudication caused by small aorta syndrome: a case report and review of literature.

Aortoiliac arterial steno-occlusions in young or middle-aged patients are relatively rare and have been reported in the literature as small aorta syndrome (SAS) or hypoplastic aortoiliac syndrome. We report the case of a 48-year-old Japanese woman with intermittent claudication caused by SAS. We performed left iliofemoral bypass grafting with a Dacron graft via a retroperitoneal approach. Bypass grafts, endarterectomy, and sympathectomy have been used for surgical management. Given that post-procedural event rates are higher for SAS than for other common atherosclerotic diseases, patients with SAS should be closely followed up after surgery.

Outcomes and morphologic changes after endovascular repair for abdominal aortic aneurysms with a severely angulated neck- a device-specific analysis.

BACKGROUND: With respect to endovascular aneurysm repair (EVAR), the development of advanced techniques and devices, namely, Cook Zenith and Gore Excluder, has helped overcome device-related problems, including device migration. Deformities of abdominal aortic aneurysms (AAAs) can influence the long-term outcome of EVAR. The post-implantation behavior of stent grafts in AAAs with a severely angulated neck (SAN) was examined. METHODS AND RESULTS: Among 190 AAA patients who underwent EVAR, 46 had SAN of more than 60 degrees. The post-implantation angle and adverse events were evaluated. Forty-one patients (89%) showed straightening of the neck angle immediately after the operation (early), with 2 types of subsequent (late) configuration changes - recoil and additional straightening. Among 34 Excluder patients, 29 showed immediate straightening, without additional straightening and 8 exhibited recoil. All 12 Zenith patients showed immediate straightening; 7 subsequently exhibited additional straightening, and none of them showed recoil. A difference (P=0.04) was noted between the 2 devices in the late angle changes. In all cases, no migration was observed at the proximal sites. CONCLUSIONS: The post-implantation configuration changes in stent placement in AAA patients with SAN were different for Excluder and Zenith. Appropriate device selection and proper planning of the procedure is necessary for EVAR.

Study Design of PROCEDURE Study. A Randomized Comparison of the Dose-Dependent Effects of Pitavastatin in Patients with Abdominal Aortic Aneurysm with Massive Aortic Atheroma: Prevention of Cholesterol Embolization during Endovascular and Open Aneurysm Repair with Pitavastatin (PROCEDURE) Study.

Outcomes of abdominal aortic aneurysm (AAA) repair have improved in the 2 decades since the emergence of endovascular aneurysm repair (EVAR). However, EVAR is considered a contraindication for shaggy aorta because of the high risk of shower embolization. Recently, statins have been implicated in preventing embolization in patients with shaggy aorta via its pleiotropic effects, including atheroma reduction and coronary artery stabilization. We selected pitavastatin, a statin with potent effects, discovered and developed by a Japanese company because it has shown excellent pleiotropic effects on atheromatous arteries in the Japanese population. A randomized comparison study of dose-dependent effects of pitavastatin in patients with AAA with massive atheromatous aortic thrombus (PROCEDURE study) has begun. PROCEDURE has an enrollment goal of up to 80 patients with AAA with massive aortic atheroma (excluding intrasac atheroma), randomly allocated into 2 groups receiving pitavastatin at a dose of 1 or 4 mg/day. The endpoints of the PROCEDURE study include change in atheroma volume, major adverse events related to shower embolization after aneurysm repair, and lipid-lowering effects. When complete, results of the PROCEDURE study should provide objective evidence to use statins preoperatively for AAA with massive aortic atheroma.

Statins reduce extensive aortic atheromas in patients with abdominal aortic aneurysms.

OBJECTIVE: Statins have been used widely to reduce dyslipidemia and recently have been reported to have pleiotropic effects such as plaque reduction and stabilization. This study retrospectively evaluated the regression of extensive thoracic atheromas ("shaggy aorta") in abdominal aortic aneurysm (AAA) patients who underwent contrast-enhanced computed tomography (CECT) before and after statin administration. MATERIALS AND METHODS: CECT was used to examine thoracic aortas of 29 patients (statin group; n = 22, non-statin group; n = 7) with extensive atheromas from the ostium of the left subclavian artery to that of the more proximal renal artery. Extensive thoracic atheroma was defined by: (1) thickness >5 mm, (2) involved circumference of thoracic aorta >50%, and (3) length >30 mm. The areas of atheroma (cm(2)) were measured before and after administration of statins, and the atheroma reduction ratio (ARR) was evaluated. RESULTS: The area of atheroma decreased after administration of statins, and the ARR was significant (P <0.01). The ARR increased with all cases in non-statin group. No complications associated with extensive atheroma were observed during the follow-up period. CONCLUSION: This pilot study indicates statins can reduce extensive thoracic atheromas and lower lipid concentrations.

Regulation of arterial lesions in mice depends on differential smooth muscle cell migration: a role for sphingosine-1-phosphate receptors.

The response of mice arteries to injury varies significantly between strains. FVB mice develop large neointimas after injury, whereas very small lesions form in C57BL/6 mice. After injury, platelet interaction with the denuded artery and early smooth muscle (SMC) replication are identical in both strains; however, the migration of SMCs differs significantly. FVB cells readily move into the developing neointima, whereas only the occasional C57BL/6 cells migrate. Injured arteries showed no difference in matrix metalloproteinases (MMP-2 and MMP-9) and plasminogen activator activities. In vitro, sphingosine-1-phosphate (S1P) in combination with platelet-derived growth factor (PDGF) stimulates migration of FVB cells but inhibits migration of C57BL/6 SMCs. Both SMCs migrate equally well to PDGF alone. One explanation is that the SMCs express different S1P receptors. Real-time polymerase chain reaction shows that FVB cells express higher levels of S1P receptor-1 (S1P(1)) compared with C57BL/6 cells, which express higher levels of S1P receptor-2 (S1P(2)). In addition, the migration of C57BL/6 cells can be increased by inhibiting S1P(2), whereas inhibiting S1P(1) expression slows the migration of FVB cells. Taken together these studies suggest that expression of S1P receptors vary within inbred mouse strains and that S1P is critical for SMC migration and lesion formation after injury.

Sphingosine 1-phosphate receptor 2 negatively regulates neointimal formation in mouse arteries.

Neointimal lesion formation was induced in sphingosine 1-phosphate (S1P) receptor 2 (S1P2)-null and wild-type mice by ligation of the left carotid artery. After 28 days, large neointimal lesions developed in S1P2-null but not in wild-type arteries. This was accompanied with a significant increase in both medial and intimal smooth muscle cell (SMC) replication between days 4 to 28, with only minimal replication in wild-type arteries. S1P2-null SMCs showed a significant increase in migration when stimulated with S1P alone and together with platelet-derived growth factor, whereas both wild-type and null SMCs migrated equally well to platelet-derived growth factor. S1P increased Rho activation in wild-type but not in S1P2-null SMCs, and inhibition of Rho activity promoted S1P-induced SMC migration. Plasma S1P levels were similar and did not change after surgery. These results suggest that activation of S1P2 normally acts to suppress SMC growth in arteries and that S1P is a regulator of neointimal development.

Evaluation of cerebral hypoperfusion by nuclear medicine imaging in a patient with Takayasu's arteritis.

In patients with Takayasu's arteritis presenting with cerebrovascular insufficiency, deciding whether and how to perform surgical intervention is difficult. We report successful extra-anatomical cerebrovascular reconstruction in a patient with Takayasu's arteritis involving the aortic arch. A 27-year-old woman was diagnosed with Takayasu's arteritis with occlusion of all three branches of the aortic arch. Single-photon emission computed tomography and positron emission tomography of the brain were useful in assessing the indication and effect of surgical treatment. Right common ilioaxillary artery bypass grafting was performed, and at 18-month follow-up the patient remained symptom-free. Extra-anatomical bypass can be a therapeutic option for surgical management of Takayasu's arteritis with aortic arch involvement.

Clinical implication of plasma level of soluble fibrin monomer-fibrinogen complex in patients with abdominal aortic aneurysm.

OBJECTIVE: We prospectively studied the clinical implication of plasma level of soluble fibrin monomer (FM)-fibrinogen complex, a recently established molecular marker reflecting thrombin activity, in patients with abdominal aortic aneurysm (AAA) undergoing elective aortic repair. METHODS: The study included 49 patients who underwent elective aneurysm repair using a gelatin-sealed or nonimpregnated Dacron prosthesis. Plasma level of soluble FM-fibrinogen complex was measured before surgery and on days 1, 3, 5, 7, and 10 postoperatively by latex agglutination assay utilizing monoclonal antibody IF-43. Plasma levels of thrombin-antithrombin complex (TAT), D-dimer, alpha2-plasmin inhibitor-plasmin complex (PIC), and fibrinogen were also evaluated. RESULTS: The preoperative level of soluble FM-fibrinogen complex showed variation in the degree of hemostatic activation, with fair correlations with TAT (r = 0.509, P < .001), D-dimer (r = 0.521, P < .001), and PIC (r = 0.579, P < .001). The patients with greater intraoperative blood loss (> or = 800 mL) showed a significantly elevated plasma level of soluble FM-fibrinogen complex preoperatively compared with those with less intraoperative blood loss (P = .009). Its postoperative fluctuation showed a similar pattern to that of TAT, reflecting the time course of coagulation activity. Gelatin impregnation of the Dacron vascular graft did not seem to influence the postoperative systemic coagulation mechanism. CONCLUSIONS: The results indicated that soluble FM-fibrinogen complex appears to be a useful diagnostic molecular marker to assess the activity of the coagulation system, and that its preoperative level may serve as a potential risk factor for intraoperative hemorrhagic diathesis in patients undergoing elective AAA repair.