Norihiko Ohura

Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice

The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel, expressed on endothelial cells and encoded by P2rx4 in mice, has a key role in the response of endothelial cells to changes in blood flow. P2rx4−/− mice do not have normal endothelial cell responses to flow, such as influx of Ca2+ and subsequent production of the potent vasodilator nitric oxide (NO). Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2rx4−/− mice. Furthermore, P2rx4−/− mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wild-type mice. Moreover, no adaptive vascular remodeling, that is, a decrease in vessel size in response to a chronic decrease in blood flow, was observed in P2rx4−/− mice. Thus, endothelial P2X4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling.

Endovascular Treatment for Infrainguinal Vessels in Patients With Critical Limb Ischemia OLIVE Registry, a Prospective, Multicenter Study in Japan With 12-Month Follow-up

Background—Recent technical advances have made endovascular treatment (EVT) an alternative first-line treatment for critical limb ischemia. Methods and Results—A prospective multicenter study was conducted to evaluate the clinical outcomes of 314 Japanese critical limb ischemia patients (mean age, 73±10 years) with infrainguinal arterial lesions who underwent EVT. Patients were enrolled from December 2009 to July 2011 and were followed-up for 12 months. The primary end point was amputation-free survival (AFS) at 12 months. Secondary end points were anatomic, clinical, and hemodynamic measures, including 12-month freedom from major adverse limb events. The 12-month AFS rate was 74%, with body mass index <18.5 (hazard ratio [HR], 2.22; P=0.008), heart failure (HR, 1.73; P=0.04), and wound infection (HR, 1.89; P=0.03) associated with a poor prognosis for AFS. The 12-month major adverse limb event-free rate was 88%, with hemodialysis (HR, 1.98; P=0.005), heart failure (HR, 1.69; P=0.02), and Rutherford classification 6 (HR, 2.25; P=0.002) associated with a poor prognosis for major adverse limb events. The median time for wound healing was 97 days, with body mass index <18.5 (HR, 0.54; P=0.03) and wound infection (HR, 0.60; P=0.04) being significant risk factors for unhealed wounds after EVT. At 12 months, 34% had undergone reintervention (bypass surgery, 2.6%; repeat EVT, 31.7%), and 73% were major adverse event–free. Conclusions—The high reintervention rate notwithstanding, EVT was an effective treatment for Japanese critical limb ischemia patients with infrainguinal disease, with satisfactory AFS and major adverse limb event-free rates. The results of this study will be helpful for the future evaluation of critical limb ischemia therapy. Clinical Trial Registration—URL: http://www.umin.ac.jp/ctr. Unique identifier: UMIN000002830.

Influence of external forces (pressure and shear force) on superficial layer and subcutis of porcine skin and effects of dressing materials: Are dressing materials beneficial for reducing pressure and shear force in tissues?

The purpose of this study was to measure the impact of external shear force and pressure on a superficial layer of skin and subcutaneous layer with an underlying bony prominence, and also to verify how the influence of these external forces can be reduced after dressings are applied. For this purpose, an experimental model was prepared, consisting of porcine skin and a Predia sensor capable of measuring pressure and shear force simultaneously. External force was applied to the skin model using a 1 kg weight consisting of metal beads. As a result, the control of the shear force value in the subcutaneous layer became approximately 35% smaller than the control in the superficial layer. The shear forces present in the subcutaneous layer were significantly reduced to within 31–45% when compared with the control values, depending on the dressing applied. Regarding the maximum pressures in the subcutaneous layer, the pressure measured following movement was 2.4 times higher in the control than the static pressure and they were also 1.3–1.8 times higher than the static pressure in all instances with the dressing tested. All the dressing materials tested proved to be effective in reducing pressure in the subcutaneous layer compared with the control. Film dressings and hydrocolloid dressings were more effective than hydropolymer and hydrocellular dressings. From the above results, we conclude that efforts made to reduce shear force and pressure may be clinically important.

Comparative study of different combinations of microvascular anastomoses in a rat model: end-to-end, end-to-side, and flow-through anastomosis.

Background: This study aimed to compare several microvascular anastomotic techniques by patency rate using a free flap model in rats. Methods: A microsurgical transfer model of a pectoral skin flap to the cervical region was used. In experiment 1, 120 rats were divided into four groups (n = 30 in each group) depending on the type of microvascular anastomotic technique. For group 1, end-to-end anastomoses were performed for arteries and veins. For group 2, end-to-side anastomoses were performed for arteries and end-to-end anastomoses were performed for veins. For group 3, flow-through anastomoses were performed for arteries and end-to-end anastomoses were performed for veins. For group 4, end-to-end anastomoses were performed for arteries and end-to-side anastomoses were performed for veins. Flap survival was assessed on day 3 and the success rates of the four groups compared. In experiment 2 (n = 10), postoperative blood flows of end-to-end and flow-through arterial anastomoses were measured. Results: In experiment 1, the success rates in groups 1, 2, 3, and 4 were 76.7, 83.3, 100, and 83.3 percent, respectively. Differences between group 3 and the other groups were statistically significant. In experiment 2, the blood flow of flow-through arterial anastomosis (1.8 ml/minute) was much higher than that of end-to-end anastomosis (0.18 ml/minute). Conclusions: Flow-through arterial anastomosis presented a higher blood flow through the anastomotic site, resulting in a higher success rate than conventional anastomoses. In veins, end-to-side anastomosis was equivalent to end-to-end anastomosis even though the diameter of the donor vein was larger than the recipient vein.

3-Year Outcomes of the OLIVE Registry, a Prospective Multicenter Study of Patients With Critical Limb Ischemia: A Prospective, Multi-Center, Three-Year Follow-Up Study on Endovascular Treatment for Infra-Inguinal Vessel in Patients With Critical Limb Ischemia.

OBJECTIVES This study sought to investigate the 3-year follow-up results of OLIVE registry patients. BACKGROUND Although favorable 12-month clinical outcomes after endovascular therapy (EVT) in OLIVE registry patients with critical limb ischemia (CLI) from infrainguinal disease have been reported, long-term results after EVT remain unknown. METHODS This was a prospective multicenter registry study that consecutively enrolled patients who received infrainguinal EVT for CLI. The primary outcome was 3-year amputation-free survival (AFS), whereas secondary outcome measures were 3-year freedom from major adverse limb events (MALE), wound-free survival, and wound recurrence rate. Prognostic predictors for each outcome were also elucidated by Cox proportional hazard regression analysis or the log-rank test. RESULTS The completion rate of 3-year follow-up was 95%. Three-year AFS, freedom from MALE, and wound-free survival rates were 55.2%, 84.0%, and 49.6%, respectively. Wound recurrence out to 3 years was 43.9%. After multivariable analysis, age (hazard ratio [HR]: 1.43, p = 0.001), body mass index ≤18.5 (HR: 2.17, p = 0.001), dialysis (HR: 2.91, p < 0.001), and Rutherford 6 (HR: 1.64, p = 0.047) were identified as predictors of 3-year major amputation or death. Statin use (HR: 0.28, p = 0.02), Rutherford 6 (HR: 2.40, p = 0.02), straight-line flow to the foot (HR: 0.27, p = 0.001), and heart failure (HR: 1.96, p = 0.04) were identified as 3-year MALE predictors. Finally, CLI due to isolated below-the-knee lesion was a wound recurrence predictor (HR: 4.28, p ≤ 0.001). Three-year survival, freedom from major amputation, and reintervention rates were 63.0%, 87.9%, and 43.2%. CONCLUSIONS In CLI patients with infrainguinal lesions, 3-year clinical results of EVT were reasonable despite high reintervention and moderate ulcer recurrence rate. (A Prospective, Multi-Center, Three-Year Follow-Up Study on Endovascular Treatment for Infra-Inguinal Vessel in Patients With Critical Limb Ischemia [OLIVE 3-Year Follow-Up Study]; UMIN000014759).

Mechanism leading to the development of pressure ulcers based on shear force and pressures during a bed operation : Influence of body types, body positions, and knee positions

Surface pressures and shear forces were measured in order to clarify the mechanism leading to the development of a pressure ulcer at five sites on the body during the operation of a bed (bed) using a device for simultaneously measuring pressure and shear force. Changes of shear force and pressure when three body types adopted different supine positions, with or without raising/bending the knees (raising the knees), were investigated and analyzed. The results are as follows: a slender body type tends to have the highest shear force at the coccygeal bone site and also has a higher surface pressure at the coccygeal and at the lateral sacral bone sites than an obese body type. On the other hand, an obese body type has a higher surface pressure at the other sites than the slender type. Shear forces at the sacrum and coccygeal bone sites can be reduced during a bed operation by raising the knees. Furthermore, shear forces can be reduced during a bed operation in a supine position by matching the bodys bending points with those of the bed or by shifting the subjects 10 cm toward the head of the bed. These new findings are clinically useful in the treatment and the prevention of the onset of pressure ulcers.

Avoiding ectropion by using the Mitek Anchor System for flap fixation to the facial bones.

The application of the Mitek Anchor System for bony fixation of the flap in the cheek area is described. The cervicofacial rotationadvancement flap is fixated to the malar bone using Mini Anchors for the purpose of diminishing the downward traction on the lower eyelid. They reduced the tension in the distal part of the flap and avoided distal-edge necrosis and ectropion. In another patient the free vascularized musculocutaneous flap, which had been grafted previously for a surgical defect in the cheek and resulted in ectropion of the lower eyelid, was fixated to the malar bone, and the ectropion was corrected. The Mitek Anchor System is useful in flap fixation to the bone because it provides a simple, fast, and reliable method for flap fixation with minimal dissection and precise placement.

Comparative study of different combinations of microvascular anastomosis types in a rat vasospasm model: versatility of end-to-side venous anastomosis in free tissue transfer for extremity reconstruction.

BACKGROUND There have been many studies comparing the patency rates of end-to-end and end-to-side microvascular anastomoses in both arteries and veins. Most of them failed to demonstrate a significant difference. The purpose of this study was to compare three different combinations of microvascular anastomoses in a rat vasospasm model, and determine which type of anastomosis is the most tolerant to vasospasm. METHODS Ninety Wistar rats were divided into three groups (n = 30 for each). In each group, a free pectoral skin flap was elevated and microsurgically transferred to the anterior cervical region. In group 1, end-to-end anastomoses were performed on both arteries and veins, in group 2 end-to-side anastomoses were performed on arteries and end-to-end anastomoses were performed on veins, and in group 3 end-to-end anastomoses were performed on arteries and end-to-side anastomoses were performed on veins. After revascularization, vasospasm was induced with topical epinephrine. Flap survival was assessed on day 3, and the success rates of the three groups were compared. RESULTS The flap success rate was 73.3% (22 of 30) in group 1, 66.7% (20 of 30) in group 2, and 96.7% (29 of 30) in group 3. The differences between groups 1 and 3 and between groups 2 and 3 were statistically significant. Overall, venous thrombosis was much more frequent than arterial thrombosis. CONCLUSIONS In a rat epinephrine-induced vasospasm model, venous thrombosis was much more frequent than arterial thrombosis. The type of arterial anastomosis did not affect the success rate, but end-to-side venous anastomosis had a higher success rate than end-to-end venous anastomosis.

Regenerative surgery for sacral pressure ulcers using collagen matrix substitute dermis (artificial dermis).

Collagen matrix substitute dermis, or artificial dermis, has recently been developed to induce angiogenesis and fibroplasia in deep, poorly vascularized tissue defects, and its use is desirable as a means of achieving effective treatment with less invasion. However, it is difficult to apply collagen matrix to pressure ulcers, because they are usually accompanied by infection with discharge of excessive amounts of exudate or pus and generally exposed to external forces that prevent graft fixation. To overcome these difficulties, the authors demonstrated a novel procedure to exclude unfavorable exudate and external forces. The procedure resulted in successful fixation of the artificial dermis and induction of regeneration in poorly vascularized defects in every case. The histologic findings provided supporting evidence that collagen matrix acts as a scaffold for reconstruction of nearly normal vascular structures coursing perpendicularly in the upper layer of normal dermis.

Clinical efficacy of basic fibroblast growth factor on pressure ulcers: case-control pairing study using a new evaluation method.

A basic fibroblast growth factor (bFGF) case and a control case whose total scores of Pressure Ulcer Healing Process‐Ohura (PUHP‐Ohura) and risk factors for pressure ulcers, and level of care for pressure ulcers were equivalent were paired. Twenty‐three such eligible pairs were enrolled in this study. Both cases in each pair were treated under conditions in which extrinsic factors such as the use of a pressure‐relief mattress and the frequency of postural change were equivalent. The efficacy of bFGF was assessed by analyzing the data obtained over time as the scores of PUHP‐Ohura for nine observation items using the SAS MIXED procedure. Treatment of pressure ulcers with bFGF accelerated wound healing over time more significantly than the control in six observation items (exudate volume, ulcer depth, granulation formation, wound edge, epithelialization, total score of the PUHP‐Ohura). These data suggest that it may be possible to evaluate drugs for the treatment of pressure ulcers using the PUHP‐Ohura wound‐assessment tool.