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Objective: This study aimed to determine the impact of infrapopliteal (IP) revascularisation establishing in line flow to the wound (IFW) on wound healing in chronic limb threatening ischaemia (CLTI), using a core laboratory assessment for wounds and in line flow., Methods: The Wound directed Angiosome RevasculaRIsation apprOach to patients with cRitical limb iSchaemia (WARRIORS) multicentre observational study enrolled patients with CLTI with tissue loss undergoing IP revascularisation in Japan, with scheduled two year follow up. The primary outcome measure was complete wound healing, defined as achievement of complete epithelialisation of all wounds without major amputation. IP revascularisation establishing IFW was defined as revascularisation after which a tibiopedal artery that actually fed an injured pedal unit was patent. The incidence of wound healing was compared between the IFW and non-IFW groups using inverse probability of treatment weighting based on the propensity score., Results: A total of 440 patients with CLTI (median age, 75 years; male, 64.1%; diabetes mellitus, 72.0%; dialysis, 57.7%) with tissue loss (Wound, Ischaemia, and foot Infection stage 4, 66.4%) who underwent IP revascularisation (endovascular procedure, n = 304; bypass grafting, n = 136) between October 2017 and June 2020 were registered. During a median follow up of 23.6 months, 51.1% achieved wound healing. Successful IP revascularisation with IFW was achieved in 68.2%. After analysis, the IFW group had a higher rate of wound healing than the non-IFW group (34.5 vs. 16.1 per 100 person years; p = .030). The association between IFW and wound healing was not statistically different between patients undergoing bypass grafting and those undergoing an endovascular procedure (p for interaction = .38). There was no statistically significant interaction effect between IFW and direct revascularisation for wound healing (p for interaction = .51)., Conclusion: IP revascularisation establishing IFW was statistically significantly associated with a higher wound healing rate in patients with CLTI., (Copyright © 2024 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: In the treatment of chronic limb-threatening ischemia (CLTI), complete wound healing is an important goal. Although foot perfusion status seems to be important for wound healing, the Global Limb Anatomic Staging System (GLASS) of the Global Vascular Guidelines does not include pedal artery status for the staging process due to the lack of sufficient evidence of its importance. This study aimed to clarify the importance of pedal perfusion status after bypass surgery., Methods: Among the 153 CLTI cases that underwent bypass distal to popliteal arteries from 2014 to 2018, 117 CLTI limbs with wounds and with sufficient pedal angiographic data were enrolled. They were classified into two groups, based on the wound status 6 months postoperatively; early wound healing group (EWG; n = 78), which achieved complete wound healing within 6 months postoperatively, and prolonged healing or unhealed wounds group (PWG; n = 39), which failed to achieve wound healing within 6 months. Various factors associated with wound healing, including the wound, ischemia, and foot infection (WIfI) classification, intraoperative graft flow, and pedal angiographic data, were analyzed. Regarding pedal angiographic data, in addition to the GLASS inframalleolar/pedal disease descriptor (IPD), newly formed classification system of the pedal circulation status in association with the location of wounds was included: pedal circulation status was classified into two groups as visualized arterial perfusion towards wounds (visualized perfusion) and non-visualized arterial perfusion towards wounds (non-visualized perfusion)., Results: Univariate analysis showed preoperative albumin (Odds ratio [OR], 0.47; 95% confidence interval [CI], 0.24-0.94; P = .027), higher WIfI clinical stage (OR, 3.88; 95% CI, 1.74-10.1; P = .0005), higher IPD (OR, 2.16; 95% CI, 1.16-4.02; P = .012), and non-visualized perfusion to wounds (OR, 5.74: 95% CI, 2.45-14.0; P < .0001) as significant for prolonged wound healing. Multivariate analysis showed higher WIfI stage (OR, 5.04; 95% CI, 1.74-14.6; P = .0029) and non-visualized perfusion to wounds (OR, 4.34; 95% CI, 1.71-11.0; P = .0021) as significant, whereas IPD was not detected as significant. Regarding blood supply to the foot, although graft flow was significantly lower in IPD-P2 than IPD-P0/P1, graft flow was similar regardless of the status of angiographic circulation to wounds, suggesting that distribution of blood supply to the wound would be more important than total amount of blood supply to the foot for wound healing., Conclusions: WIfI clinical stage and pedal circulatory environment were important factors for wound healing after bypass surgery. Pedal anatomical classification system including perfusion status would be important for decision making in CLTI treatment., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Infected native aneurysms (INAs) of the abdominal aorta and iliac arteries are uncommon, but potentially fatal. Endovascular aneurysm repair (EVAR) has recently been introduced as a durable treatment option, with outcomes comparable to those yielded by conventional open repair. However, owing to the rarity of the disease, the strengths and limitations of each treatment remain uncertain. The present study aimed to separately assess post-open repair and post-EVAR outcomes and to clarify factors affecting the short-term and late prognosis after each treatment., Methods: Using a nationwide clinical registry, we investigated 600 patients treated with open repair and 226 patients treated with EVAR for INAs of the abdominal aorta and/or common iliac artery. The relationships between preoperative or operative factors and postoperative outcomes, including 90-day and 3-year mortality and persistent or recurrent aneurysm-related infection, were examined., Results: Prosthetic grafts were used in >90% of patients treated with open repair, and in situ and extra-anatomic arterial reconstruction was performed in 539 and 57 patients, respectively. Preoperative anemia and imaging findings suggestive of aneurysm-enteric fistula were independently associated with poor outcomes in terms of both 3-year mortality (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.01-2.62; P = .046, and HR, 2.24; 95% CI, 1.12-4.46; P = .022, respectively) and persistent or recurrent infection (odds ratio [OR], 2.16; 95% CI, 1.04-4.49; P = .039, and OR, 4.96; 95% CI, 1.81-13.55; P = .002, respectively) after open repair, whereas omental wrapping or packing and antibiotic impregnation of the prosthetic graft for in situ reconstruction contributed to improved 3-year survival (HR, 0.60; 95% CI, 0.39-0.92; P = .019, and HR, 0.53; 95% CI, 0.32-0.88; P = .014, respectively). Among patients treated with EVAR, abscess formation adjacent to the aneurysm was significantly associated with the occurrence of persistent or recurrent infection (OR, 2.24; 95% CI, 1.06-4.72; P = .034), whereas an elevated preoperative white blood cell count was predictive of 3-year mortality (HR, 1.77; 95% CI, 1.00-3.13; P = .048)., Conclusions: Profiles of prognostic factors differed between open repair and EVAR in the treatment of INAs of the abdominal aorta and common iliac artery. Open repair may be more suitable than EVAR for patients with concurrent abscess formation., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Heatwaves often cause mass mortality of organisms in seagrass areas, and they eventually alter some ecological functions of seagrass ecosystems. In subarctic regions, however, the effects of heatwaves on seagrass areas are still unclear. In a subarctic lagoon of northern Japan, we examined the effects of heatwaves on the Hokkai shrimp, Pandalus latirostris, a commercially exploited species distributed in seagrass areas of northern Japan and eastern Russia. A long-term survey of the surface water temperature in the lagoon clarified a gradual increase in the frequency and intensity of heatwave events since 1999. Surveys of the water temperature at a seagrass area in the lagoon during summer have also demonstrated that the maximum water temperature had been exceeding 25 °C, unusually high for this location, regardless of water depth. These results indicate that the effects of heatwaves in seagrass areas in a subarctic region had become as severe as those in tropical and temperate regions. We also experimentally evaluated the effects of this unusually high water temperature (25 °C) on the survival of P. latirostris by changing the length of exposure time. Some individuals suffered damage to their intestinal mucosal structure after exposure for 12 h or longer, and all individuals died after exposure for 120 h. Our results suggest that heatwaves possibly cause mass mortality in P. latirostris in the following sequence: heat stress, damage to the intestinal epithelial mucosal structure, degradation of nutrient absorption and immunological function of the intestine, energy deficiency and disease infection, and finally mortality. This study, conducted in subarctic closed waters, concludes that it is essential to become familiar with not only trends in heatwaves but also the intermittent occurrence of unusually high water temperature in seagrass areas in order to better understand the process of mortality of organisms that inhabit these ecosystems., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Surgical treatment is an established method for popliteal artery entrapment syndrome (PAES), which, however, mainly derives from single centre experiences where PAES cases are centralised and treated periodically. This study evaluated clinical outcomes of surgical treatment for PAES in a clinical setting where PAES cases were not centralised., Methods: Multicentre, retrospective cohort study using a national clinical registry. From a Japanese nationwide clinical registry, data for patients who underwent surgical treatment for PAES between 2013 and 2018, including 58 limbs from 41 institutes, were retrieved and evaluated. Patency was analysed using Kaplan-Meier curves., Results: The mean patient age was 36 ± 19 years, 78% were male, and the incidence of PAES was 0.24 limbs/centre/year, reflecting a clinical setting where PAES cases are not centralised. The most frequent arterial symptom was intermittent claudication (90%). Computed tomography was performed in 57 limbs (98%) for the diagnosis, however active manoeuvres such as dorsiflexion and plantarflexion during the examination was performed in only 13 limbs (22%), and occlusion of the popliteal artery was present in 38 limbs (66%) at diagnosis. Regarding surgical treatment, myotomy alone was performed in only seven limbs (12%), and other limbs were revascularised. Mean follow up was 26 ± 20 months, and surgical treatment was effective as it relieved symptoms in > 96% of limbs, with five year primary and secondary patency of the surgical treatment for PAES of 72% and 93%, respectively., Conclusion: Results of surgical treatment were acceptable even in a clinical setting where PAES cases were not centralised. However, a low incidence of active manoeuvres performed during the examination and a high incidence of occlusion at diagnosis suggests there may be delayed or underdiagnosis of PAES in Japan, and increased awareness for PAES is warranted., (Copyright © 2023 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to create prediction models for two year overall survival (OS) and amputation free survival (AFS) after revascularisation in patients with chronic limb threatening ischaemia (CLTI)., Methods: This was a retrospective analysis of prospectively collected multicentre registry data (JAPAN Critical Limb Ischaemia Database; JCLIMB). Data from 3 505 unique patients with CLTI who had undergone revascularisation from 2013 to 2017 were extracted from the JCLIMB for the analysis. The cohort was randomly divided into development (2 861 patients) and validation cohorts (644 patients). In the development cohort, multivariable risk models were constructed to predict two year OS and AFS using Cox proportional hazard regression analysis. These models were applied to the validation cohort and their performances were evaluated using Harrell's C index and calibration plots., Results: Kaplan-Meier estimates of two year OS and AFS post-revascularisation in the whole cohort were 69% and 62%, respectively. Strong predictors for OS consisted of age, activity, malignant neoplasm, chronic kidney disease (CKD), congestive heart failure (CHF), geriatric nutritional risk index (GNRI), and sex. Strong predictors for AFS included age, activity, malignant neoplasm, CKD, CHF, GNRI, body temperature, white blood cells, urgent revascularisation procedure, and sex. Prediction models for two year OS and AFS showed good discrimination with Harrell's C indexes of 0.73 (95% confidence interval [CI] 0.69 - 0.77) and 0.72 (95% CI 0.68 - 0.76), respectively CONCLUSION: Prediction models for two year OS and AFS post-revascularisation in patients with CLTI were created. They can assist in determining treatment strategies and serve as risk adjustment modalities for quality benchmarking for revascularisation in patients with CLTI at each facility., (Copyright © 2022 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

We developed a small fluorescence microplate reader with an organic photodiode (OPD) array. The OPD array has nine OPDs that have a large light receiving area (9.62 mm 2 per one OPD). Since the OPD array is fabricated on a flat glass plate, it can be placed just below microwells and can detect fluorescence emitted through the entire surface of the microwell bottom. The analytical performance of the developed plate reader was evaluated by measuring an aqueous solution of resorufin. The limit of detection (LOD) for resorufin (0.01-0.05 μM) was lower than that obtained with a plate reader equipped with nine inorganic photodiodes developed in a previous study (0.30 μM) and a commercially available microplate reader (0.16 μM). These results indicate that the large light receiving area improves the detection performance of the system. In addition, the developed reader was successfully used to quantify immunoglobulin A (IgA) in human saliva. The LOD for IgA was estimated to be 1.2 ng/mL, which is low enough to objectively evaluate human stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The current study aimed to reveal clinical features and prognosis of asymptomatic contralateral limbs in patients undergoing revascularization for chronic limb-threatening ischemia (CLTI)., Methods: We analyzed a database of 520 CLTI patients registered in a prospective, multicenter registry in Japan. Severe ischemia in asymptomatic contralateral limbs was determined as the Wound, Ischemia, and foot Infection (WIfI) classification system Ischemia (I) grade 2/3., Results: The prevalence of diabetes mellitus and dialysis-dependent renal failure was 74.2% and 53.5%, respectively. Asymptomatic limbs accounted for 65.0% [95% confidence interval (CI), 60.9-69.1%] of the overall population, and 55.0% (95% CI, 49.6-60.4%) of the asymptomatic contralateral limbs had WIfI I-2/3. The multivariate analysis identified age ≥65 years, dialysis-dependent renal failure, WIfI I-3 in the index limb, and loss of pressure sensation in the contralateral limb as independent risk factors for WIfI I-2/3 in asymptomatic contralateral limbs (all p < 0.05). The 3-year cumulative incidence rate of major adverse limb events (MALE) in asymptomatic contralateral limbs was 19.3% (95% CI, 15.1-23.7%), whereas that of all-cause mortality was 46.9% (95% CI, 41.0-52.5%). The corresponding rate including a composite of mortality and MALE was 58.8% (95% CI, 52.9-64.6%). In asymptomatic contralateral limbs, the adjusted hazard ratio of WIfI I-2/3 versus I-0/1 was 1.53 (95% CI, 1.11-2.10) for a composite of mortality and MALE, 1.96 (95% CI, 1.14-3.36) for MALE, and 1.37 (95% CI, 0.95-1.96) for mortality (p = 0.009, 0.015, and 0.091, respectively)., Conclusions: Two-thirds of CLTI patients had an asymptomatic contralateral limb, and approximately half of the asymptomatic contralateral limbs were exposed to severe ischemia. Older age, dialysis-dependent renal failure, WIfI I-3 in the index limb, and loss of pressure sensation in the contralateral limb were independently associated with severe ischemia in asymptomatic contralateral limbs. In addition to mortality, MALE commonly occurred in asymptomatic contralateral limbs, especially with WIfI I-2/3., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: Chronic limb threatening ischaemia (CLTI) decreases life expectancy and impairs health related quality of life (HR-QOL). Revascularisation is needed to relieve ischaemia and salvage limbs. Although a major goal of CLTI treatment is maintaining QOL, little information is available about changes of HR-QOL over time after revascularisation. HR-QOL with survival after revascularisation for CLTI was assessed., Methods: The clinical database of the Surgical reconstruction versus Peripheral INtervention in pAtients with critical limb isCHemia (SPINACH), a prospective multicentre observational study, was analysed. Outcome measures were disease specific QOL per the Vascular Quality of Life (VascuQOL) questionnaire and the Short Form (SF) 36 evaluated generic QOL, which were assessed at baseline and three, 12, 24, and 36 months. The outcome measure was change of QOL from baseline. The minimally important difference (half a standard deviation from baseline) was used as the cut off point for improved, worsened, and unchanged QOL., Results: Overall QOL was improved in 61% of patients for the VascuQOL and approximately 40% for the SF-36 component summaries at three months. However, these proportion gradually decreased to 21% - 31% at three years. In contrast, the proportion of deceased patients gradually increased over the three year follow up. Multivariable analysis revealed that pre-operative non-ambulatory status was inversely associated with improved QOL for the three month VascuQOL and SF-36 mental component summary, and surgical reconstruction was positively associated with these measurements. Advanced age and renal failure were inversely associated with improved QOL for the SF-36 mental component summary and VascuQOL at one to three years., Conclusion: Revascularisation improved QOL. However, patients with non-ambulatory status exhibited a negative association with improved QOL at three months, and advanced age and renal failure limited benefits one to three years after revascularisation. Accumulating QOL data will be essential for post-revascularisation QOL estimation. Pre-operative assessment, including estimated QOL, is important in shared decision making for patient oriented outcomes in the treatment of CLTI patients., (Copyright © 2021 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to assess the impact of baseline and updated nutritional status on prognosis in patients with chronic limb threatening ischaemia (CLTI) undergoing revascularisation., Methods: The clinical database of the Surgical reconstruction versus Peripheral INtervention in pAtients with critical limb isCHemia (SPINACH) study, a prospective, multicentre, observational study, was used. The current analysis included 499 patients who underwent endovascular therapy or surgical reconstruction for CLTI. Nutritional status at baseline was evaluated using the Geriatric Nutritional Risk Index (GNRI; baseline GNRI). A GNRI <82 points indicates major nutrition related risk. GNRI was also calculated at 1, 3, 6, 12, 24, and 36 months after revascularisation (updated GNRI). The association between baseline and updated GNRIs and the mortality risk was analysed with the Cox regression model., Results: Mean ± standard deviation (SD) GNRI at baseline was 89.9 ± 9.8 points. The proportion of patients alive with a GNRI ≥82 points was 78% (95% confidence interval [CI] 74-81) at baseline but gradually decreased during follow up, finally reaching 19% (95% CI 0-42) at 36 months. In patients with a GNRI <82 points at baseline, a GNRI of ≥82 points was increased to 37% (95% CI 6-68) 12 months after revascularisation. In the multivariable analysis, baseline and updated GNRIs were associated with a reduced mortality risk independently of each other; the adjusted hazard ratios per 1 SD were 0.80 (95% CI 0.65-0.98; p = .031) and 0.66 (95% CI 0.49-0.91; p = .015), respectively. Similar findings were observed when nutritional status was evaluated using the Controlling Nutritional Stats (CONUT) score, except for the association between its updated value and mortality risk, which marginally lost significance., Conclusion: There was still room for improvement in nutritional status after revascularisation for patients with CLTI. Updated GNRI was associated with death independently of baseline GNRI., (Copyright © 2020 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Background: In chronic limb-threatening ischemia, maintenance or recovery of ambulatory function is an important goal of treatment. This study aimed to develop a predictive model for ambulatory ability 1 year after bypass based on preoperative risk factors, including the Wound, Ischemia, and foot Infection (WIfI) classification., Methods: We analyzed 146 patients with chronic limb-threatening ischemia (154 limbs) who underwent bypass to below the knee arteries. The patients were classified into 2 groups based on ambulatory status 1 year postoperatively: postoperative ambulation (99 patients, 104 limbs) and postoperative nonambulation (47 patients, 50 limbs). Various factors associated with postoperative ambulation were analyzed and a predictive model of postoperative ambulation was developed., Results: Multivariate logistic regression analysis detected preoperative nonambulatory status, functional nonindependence in daily living, older age, WIfI wound grade 3, chronic obstructive pulmonary disease, and hemodialysis as independent risk factors for postoperative nonambulation. The predictive scoring model (scores ranging from -5.0 to 4.4) comprising these risk factors discriminated the postoperative ambulatory status well: the probabilities of postoperative ambulatory ability were ≥85% in those with a score ≤-2, 50% in those with a score of zero, and ≤15% in those with a score ≥2. The area under the receiver operating characteristic curve was 0.898, indicating good performance of the model., Conclusions: Preoperative nonambulatory status, functional nonindependence, advanced age, high WIfI wound grade, chronic obstructive pulmonary disease, and hemodialysis were important predictors of postoperative nonambulatory status. The predictive model will help us identify patients who will benefit from bypass surgery., (Copyright © 2020. Published by Elsevier Inc.)

B-cell activating factor (BAFF) is known as a cytokine responsible for survival and activation of B cells. However, involvement of the molecule in IgG antibody production during infection remains elusive. In this study, dependency of antibody production in Leishmania infection on BAFF was examined by using BAFF-knockout (BAFF-KO) mice. When BAFF-KO mice were infected with L. major, there was no significant difference in lesion development or parasite burden from those in infected wildtype mice. In contrast, levels of IgG antibodies to Leishmania crude antigen were lower in BAFF-KO mice, suggesting that antibody production during L. major infection is BAFF-dependent. ELISA using defined leishmanial antigens demonstrated that the influence of BAFF on antibody production during L. major varies depending on antigens; IgG production to tandem repeat proteins were more affected by BAFF than non-repeat antigens. On the contrary, all of the defined antigens tested were strongly affected by BAFF for IgG antibody production during L. donovani infection. These results suggest degree of BAFF contribution to antibody production during infection is variable depending on the type of infection and even on the type of antigen in a given infection. These results may explain contradictory roles of BAFF in antibody production in previous works., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Intimal hyperplasia (IH) is the main cause of therapeutic failure after vascular and endovascular surgery. However, there is currently no targeted therapy for the treatment of IH. We recently reported that the inhibition of cyclic adenosine monophosphate response element (CRE) binding protein (CREB) activation is important in vein graft IH. We focused on a decoy oligodeoxynucleotide (ODN) therapeutic strategy for suppressing IH as a clinical application. The objective of this study was to confirm the therapeutic effect of a CRE decoy ODN in an animal model as a novel therapy for preventing intimal hyperplasia as the first step of the preclinical study of our strategy., Methods: We designed two phosphorothioate CREs and two scramble decoy ODNs and screened them using a CREB transcription assay to check their ability to bind to a CRE sequence. We chose a CRE decoy ODN with high first-binding ability and transfected it into vascular smooth muscle cells (VSMCs) in vitro. Proliferation and migration were assessed using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays and modified Boyden chamber assays. We examined CRE activity using a luciferase reporter gene assay. We assessed the expression of messenger RNAs by quantitative real-time polymerase chain reaction. In a wire-injury mouse model (C57BL6, n = 6), CRE decoy ODN was transfected into the injured vessel wall using an ultrasound-sonoporation method in vivo. Mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3) and four and a half LIM domains 5 (FHL5) expression of pregrafting vein remnants were assessed by immunohistologic analyses., Results: Compared with scramble decoy ODN, the selected CRE decoy ODN could significantly decrease CRE activity (mean ± standard error of the mean: 0.20 ± 0.03 vs 1.00 ± 0.16, n = 6; P < .05) as shown by a luciferase reporter gene assay, VSMC proliferation (0.73 ± 0.04 vs 0.89 ± 0.02, n = 6; P < .05) and migration (96.4 ± 6.1 vs 311.4 ± 19.1 migrated VSMCs/well, n = 6; P < .05) after 24-hour transfection. The CRE decoy ODN significantly suppressed the formation of IH at injured vessel walls in an animal model, as analyzed by pathologic staining (0.20 ± 0.02 vs 0.56 ± 0.08, area of the intima/area of the artery vs the control after 21 days' transfection, n = 6; P < .05). Furthermore, MAPKAPK3 and FHL5, which are CREB activators, were significantly expressed in pregrafting vein remnants in diabetes mellitus patients., Conclusions: CREB-CRE signaling is an important mechanism of IH formation, and CRE decoy therapy can help preventing IH. This study is the first part of the preclinical study of our strategy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Graft flow (GF) seems to be an important prognostic predictor in distal bypass for critical limb ischemia, but previous studies have failed to clarify the association between GF and the graft prognosis. GF differs significantly among grafts, and each graft seems to have an optimal GF depending on various factors. We hypothesized that comparison between the measured GF (mGF) and optimal estimated GF (eGF) would be important in predicting graft prognosis. Herein, we aimed to develop a GF predictive equation by assessing GF determinants and to validate the equation against a clinical dataset., Methods: A total of 198 distal bypasses with vein grafts for critical limb ischemia from 2011 to 2016 were enrolled. Of these grafts, 135 normal grafts without any abnormalities on early postoperative ultrasound examination were used to develop and validate the equation. Various anatomic and patient-related factors were analyzed to detect GF determinants with stepwise selection, and the GF predictive equation was developed with multiple linear regression analysis. After developing the equation, all 198 grafts were categorized into two groups according to the equation developed based on data from the 135 normal grafts as follows: optimal flow grafts (OFGs), in which mGF > eGF - 14.6, and suboptimal flow grafts (SFGs), in which mGF < eGF - 14.6. The cutoff value of 14.6 was determined using receiver operating characteristic curves to detect graft abnormalities. By comparing OFGs and SFGs, the efficacy of the equation in predicting bypass abnormalities and graft prognosis was assessed., Results: The GF determinants were runoff, hemodialysis (HD), diabetes mellitus (DM), and graft quality (GQ). The predictive equation was estimated as follows: GF(ml/min)=(32.9×run-off)+(9.9×GQ)-(13.0×DM)-(35.1×HD)+12.1 (R 2  = 0.71, coefficient: runoff and GQ, 3 [good], 2 [fair], 1 [poor]; DM and HD, 1 [yes], 0 [no]). In the efficacy assessment of the equation, SFGs showed a significantly higher rate of bypass abnormalities (64.0% vs 12.2%; P < .0001), graft intermediate stenosis (10.7% vs 1.6%; P = .0071), graft critical stenosis (28.0% vs 3.2%; P < .0001), and early graft occlusion (17.3% vs 4.3%; P = .0037) than OFGs and were associated with a higher rate of revision surgery within 2 years after surgery (50.7% vs 34.2%; P = .026). SFGs also showed significantly lower primary patency rates (P < .0001) and secondary patency rates (P = .0005)., Conclusions: GF was well-estimated with runoff, GQ, and the presence of DM and HD. A comparison between mGF and eGF, calculated with the equation, will help to detect bypass abnormalities and determine the necessity of additional intraoperative procedures and, thus, achieve optimal outcomes., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: It is well known that the clinical outcome of patients with critical limb ischemia (CLI) is poor. However, the relationship between stress-related hormone levels and CLI outcome remains unclear. The aim of this study was to reveal the association of stress hormones with the risk of a perioperative major adverse cardiovascular event (pMACE) in CLI patients undergoing surgical and endovascular revascularization., Methods: The study analyzed 467 CLI patients who had levels of stress-related hormones (epinephrine, norepinephrine, dopamine, and cortisol) measured before undergoing revascularization. The primary end point was pMACE, including all-cause mortality, myocardial infarction, and stroke within 30 days after revascularization. Propensity score matching was used to try to control for potential confounding., Results: Of the 467 patients analyzed, pMACE was observed in 21 patients (4.5%). The crude comparison of stress-related hormone levels between those with and those without pMACE showed that those with pMACE had a higher level of epinephrine, dopamine, and cortisol compared with those without pMACE. After propensity matching (20 patients with pMACE and 192 patients without pMACE), epinephrine and cortisol levels were significantly higher in those with pMACE. Multivariate analysis confirmed that both epinephrine and cortisol levels were related to the risk of pMACE independently of each other. The Cox proportional hazards regression model demonstrated that both hormones were associated with 30-day mortality but not with longer term mortality., Conclusions: Stress-related hormone (epinephrine and cortisol) levels were significantly associated with the risk of pMACE in CLI patients undergoing revascularization. Both hormones were related to 30-day mortality., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: Surgical revascularisation to accomplish limb salvage remains preferable in some patients with chronic limb threatening ischaemia (CLTI). The aim of this study was to evaluate the effectiveness and safety of ultrasound guided lower extremity nerve blockade (UGNB) in infragenicular bypass surgery (IGBS)., Methods: This was a single centre, retrospective clinical study. Fifty-nine patients with CLTI (67 limbs) who underwent IGBS under UGNB (femoral and sciatic nerve blockade) at Asahikawa Medical University between January 2012 and December 2017 were compared with patients with CLTI (137 limbs) who underwent IGBS under general anaesthesia (GA) over the same period. Propensity score matching based on pre-operative comorbidities was used to minimise background differences of the two groups., Results: Fifty-six pairs of CLTIs were matched and analysed (55% dialysis dependent). Procedure duration was similar between the two groups, but intraoperative catecholamine index and intravenous fluid volume were lower with UGNB compared with GA (2.9 ± 4.6 vs. 5.9 ± 6.5; p < .01 and 1831 ± 990 vs. 2335 ± 931 mL; p < .01, respectively). The mean arterial blood pressure during induction of anaesthesia was significantly decreased with GA. Post-operatively, the time period to resume a clear liquid and solid food diet was significantly shorter with UGNB (P<0.01 for both outcome measures). Intravenous fluid volume was significanlty lower, while cardiac complications and delirium, based on the NEECHAM confusion scale, occurred significantly less often with UGNB than GA. These significant differences show advantages of UGNB compared to GA. No mortality or major amputations were observed in either group. Early graft thrombosis was observed in five limbs (8.9%) with UGNB and in four limbs with GA (7.1%) (p = .73)., Conclusions: UGNB has advantages for intra- and post-operative management and could be a useful method to prevent peri-operative complications for high risk patients with CLTI. To ensure the effectiveness of UGNB for IGBS for future indications, a randomised study is required., (Copyright © 2019 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Guideline Summary: Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative., (Copyright © 2019 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: Venous valves are essential but are prone to injury, thrombosis, and fibrosis. We compared the behavior and gene expression of smooth muscle cells (SMCs) in the valve sinus vs nonvalve sites to elucidate biologic differences associated with vein valves., Methods: Tissue explants of fresh human saphenous veins were prepared, and the migration of SMCs from explants of valve sinus vs nonvalve sinus areas was measured. Proliferation and death of SMCs were determined by staining for Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling. Proliferation and migration of passaged valve vs nonvalve SMCs were determined by cell counts and using microchemotaxis chambers. Global gene expression in valve vs nonvalve intima-media was determined by RNA sequencing., Results: Valve SMCs demonstrated greater proliferation in tissue explants compared with nonvalve SMCs (19.3% ± 5.4% vs 6.8% ± 2.0% Ki67-positive nuclei at 4 days, respectively; mean ± standard error of the mean, five veins; P < .05). This was also true for migration (18.2 ± 2.7 vs 7.5 ± 3.0 migrated SMCs/explant at 6 days, respectively; 24 veins, 15 explants/vein; P < .0001). Cell death was not different (39.6% ± 16.1% vs 41.5% ± 16.0% terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, respectively, at 4 days, five veins). Cultured valve SMCs also proliferated faster than nonvalve SMCs in response to platelet-derived growth factor subunit BB (2.9 ± 0.2-fold vs 2.1 ± 0.2-fold of control, respectively; P < .001; n = 5 pairs of cells). This was also true for migration (6.5 ± 1.2-fold vs 4.4 ± 0.8-fold of control, respectively; P < .001; n = 7 pairs of cells). Blockade of fibroblast growth factor 2 (FGF2) inhibited the increased responses of valve SMCs but had no effect on nonvalve SMCs. Exogenous FGF2 increased migration of valve but not of nonvalve SMCs. Unlike in the isolated, cultured cells, blockade of FGF2 in the tissue explants did not block migration of valve or nonvalve SMCs from the explants. Thirty-seven genes were differentially expressed by valve compared with nonvalve intimal-medial tissue (11 veins). Peptide-mediated inhibition of SEMA3A, one of the differentially expressed genes, increased the number of migrated SMCs of valve but not of nonvalve explants., Conclusions: Valve compared with nonvalve SMCs have greater rates of migration and proliferation, which may in part explain the propensity for pathologic lesion formation in valves. Whereas FGF2 mediates these effects in cultured SMCs, the mediators of these stimulatory effects in the valve wall tissue remain unclear but may be among the differentially expressed genes discovered in this study. One of these genes, SEMA3A, mediates a valve-specific inhibitory effect on the injury response of valve SMCs., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to elucidate the efficacy of paramalleolar or inframalleolar bypass (PIMB) in hemodialysis-dependent (HD) patients with critical limb ischemia (CLI) and nonhemodialysis-dependent (NHD) patients in terms of clinical outcomes., Methods: Between January 2000 and December 2013, there were 333 consecutive arteriosclerosis obliterans patients with CLI who underwent 401 PIMB procedures for limb salvage (LS). Of the 333 patients, 188 (56.5%) were HD patients. Vein grafts were exclusively used, and 172 paramalleolar and 229 inframalleolar bypasses were performed. Five-year primary and secondary cumulative graft patency, LS, and amputation-free survival (AFS) rates were compared between the two groups, and the independent determinants of these outcomes were identified in each group., Results: The 5-year primary and secondary cumulative graft patency rates were 53% and 82% in HD patients and 69% and 92% in NHD patients (primary cumulative graft patency, P < .05; secondary cumulative graft patency, nonsignificant), respectively. The LS rates were 87% and 99% (P < .01) in HD patients and NHD patients, respectively. Overall, 48% and 70% of HD and NHD patients were ambulatory before PIMB (P < .01), and 73% and 85% of HD and NHD patients were ambulatory 12 months after PIMB (including 1-year survivors; nonsignificant), respectively, demonstrating drastic post-PIMB improvement in HD patients. The 5-year AFS rates in the HD and NHD groups were 27% and 69% (P < .01), respectively, demonstrating very poor AFS rates in HD patients. In HD patients, factors negatively associated with AFS were female gender (hazard ratio [HR], 2.102; 95% confidence interval [CI], 1.254-3.524), history of congestive heart failure (HR, 2.075; 95% CI, 1.395-3.085), and preoperative nonambulatory status (HR, 1.974; 95% CI, 1.305-2.986), whereas older age (HR, 2.601; 95% CI, 1.372-4.931) and history of congestive heart failure (HR, 2.928; 95% CI, 1.496-5.731) were identified as independent factors negatively associated with AFS in NHD patients., Conclusions: The use of PIMB for CLI was associated with excellent LS rates in both HD and NHD patients with low operative mortality and complications. However, the AFS rate observed in HD patients was significantly lower than that observed in NHD patients, indicating the necessity of a specific management program to improve AFS after LS in HD patients., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

B-cell activating factor (BAFF) is a critical regulator for B-cell development and differentiation. We previously reported elevation of serum BAFF levels in patients with visceral leishmaniasis (VL). In this study, we examined if BAFF is involved in pathologies during infection of Leishmania donovani. BALB/cA mice infected with L. donovani showed significant elevation in serum BAFF and IgG levels as seen in VL patients. In contrast, elevation of serum IgG by L. donovani infection was significantly suppressed in BAFF-deficient mice. The spleen weight of the BAFF-deficient mice after infection was significantly lower than that of the infected wild-type mice, whereas comparable degree of hepatomegaly and anemia were observed in those mice. In the enlarged spleen of L. donovani-infected wild-type mice, increase of CD19 + lymphocytes was more prominent than that of CD3 + cells, suggesting the contribution of B cell increase to splenomegaly during VL. Besides, increase of CD19 + lymphocytes was not found in BAFF-deficient mice after L. donovani infection. Taken together, these results suggest that BAFF is involved in strong B cell activation, which has a pathological role in splenomegaly but not in hepatomegaly or anemia, during VL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: The authors sought to investigate the prognostic impact of revascularization for poor-risk CLI patients in real-world settings., Background: Critical limb ischemia (CLI) is often accompanied with various comorbidities, and frailty is not rare in the population. Although previous studies suggested favorable outcomes of revascularization for CLI patients, those studies commonly included the healthier, that is, less frail patients., Methods: This was a multicenter prospective observational study, registering patients who presented with CLI and who required assistance for their daily lives because of their disability in activities of daily living (ADL) and/or impairment of cognitive function. Revascularization was either planned (revascularization group) or not planned (non-revascularization group). The primary endpoint was 1-year survival, and was compared between the revascularization and non-revascularization groups, using the propensity score-matching method., Results: Between January 2014 and April 2015, a total of 662 patients were registered, of those 100 non-revascularization patients were included. A total of 625 patients (94.4%) completed the 1-year follow-up. Death was observed in 223 patients (33.7%). After propensity score matching, the 1-year survival rate was 55.9% in the revascularization group versus 51.0% in the non-revascularization group, with no significant difference (p = 0.120). In the subgroups alive at 1 year after revascularization, health-related quality of life was significantly improved compared with baseline, whereas ADL scores were unchanged from baseline and still remained significantly worse than before CLI onset., Conclusions: The 1-year overall survival rate was not significantly different between the revascularization and non-revascularization groups in poor-risk CLI patients. (Poor-Risk Patients With and Without Revascularization Therapy for Critical Limb Ischemia; [PRIORITY Registry]; UMIN000012871)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Markers containing dyes such as crystal violet (CAS 548-62-9) are routinely used on the adventitia of vein bypass grafts to avoid twisting during placement. Because little is known about how these dyes affect vein graft healing and function, we determined the effect of crystal violet on cell migration and proliferation, which are responses to injury after grafting., Methods: Fresh human saphenous veins were obtained as residual specimens from leg bypass surgeries. Portions of the vein that had been surgically marked with crystal violet were analyzed separately from those that had no dye marking. In the laboratory, they were split into easily dissected inner and outer layers after removal of endothelium. This cleavage plane was within the circular muscle layer of the media. Cell migration from explants was measured daily as either (1) percentage of migration-positive explants, which exclusively measures migration, or (2) number of cells on the plastic surrounding each explant, which measures migration plus proliferation. Cell proliferation and apoptosis (Ki67 and TUNEL staining, respectively) were determined in dye-marked and unmarked areas of cultured vein rings. The dose-dependent effects of crystal violet were measured for cell migration from explants as well as for proliferation, migration, and death of cultured outer layer cells. Dye was extracted from explants with ethanol and quantified by spectrophotometry., Results: There was significantly less cell migration from visibly blue compared with unstained outer layer explants by both methods. There was no significant difference in migration from inner layer explants adjacent to blue-stained or unstained sections of vein because dye did not penetrate to the inner layer. Ki67 staining of vein in organ culture, which is a measure of proliferation, progressively increased up to 6 days in nonblue outer layer and was abolished in the blue outer layer. Evidence of apoptosis (TUNEL staining) was present throughout the wall and not different in blue-stained and unstained vein wall segments. Blue outer layer explants had 65.9 ± 8.0 ng dye/explant compared with 2.1 ± 1.3 for nonblue outer layer explants. Dye applied in vitro to either outer or inner layer explants dose dependently inhibited migration (IC50∼10 ng/explant). The IC50s of crystal violet for outer layer cell proliferation and migration were 0.1 and 1.2 μg/mL, whereas the EC50 for death was between 1 and 10 μg/mL., Conclusions: Crystal violet inhibits venous cell migration and proliferation, indicating that alternative methods should be considered for marking vein grafts., (Copyright © 2016 Society for Vascular Surgery. All rights reserved.)

Surgical treatment for popliteal artery cystic adventitial disease (PACAD) is still controversial. PACAD often occurs in young or middle-aged adults. Therefore, the maintenance of graft patency for very long periods is a concern if a prosthesis is used. Because the intima is intact in PACAD patients with popliteal artery stenosis, a treatment that preserves the healthy intima is ideal. We describe the cases of 3 patients who underwent cystic excision for PACAD with severe stenosis. No recurrence was observed for up to 11 years, and these long-term results revealed that cystic excision could be reconsidered as one of the first-line therapeutic methods., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Intimal hyperplasia (IH) is the main cause of vein graft stenosis or failure after bypass surgery. Basic investigations are proceeding in an animal model of mechanically desquamated arteries, and numerous molecules for potential IH treatments have been identified; however, neither insights into the mechanism of IH nor substantially effective treatments for its suppression have been developed. The goals of the present study are to use human vein graft samples to identify therapeutic target genes that control IH and to investigate the therapeutic efficacy of these candidate molecules in animal models., Methods: Using microarray analysis of human vein graft samples, we identified two previously unrecognized IH-related genes, mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3) and four-and-a-half LIM domains 5 (FHL5)., Results: Transfer of either candidate gene resulted in significantly elevated vascular smooth muscle cell (VSMC) proliferation and migration. Interestingly, cotransfection of both genes increased VSMC proliferation in an additive manner. These genes activated cyclic adenosine monophosphate response-element (CRE) binding protein (CREB), but their mechanisms of activation were different. MAPKAPK3 phosphorylated CREB, but FHL5 bound directly to CREB. A CREB dominant-negative protein, KCREB, which blocks its ability to bind CRE, repressed VSMC proliferation and migration. In a wire-injury mouse model, gene transfer of KCREB plasmid significantly repressed IH. In this vessel tissue, CRE-activated gene expression was repressed. Furthermore, we confirmed the changes in MAPKAPK3 and FHL5 expression using vein graft samples from eight patients., Conclusions: We successively identified two previously unrecognized IH activators, MAPKAPK3 and FHL5, using human vein graft samples. Gene transfer of KCREB repressed IH in an animal model. Inhibition of CREB function is a promising gene therapy strategy for IH., (Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: To preoperatively determine candidates at definitive risk of postoperative delirium (POD), we identified relevant factors in patients with arteriosclerosis obliterans who underwent bypass surgery., Design: A prospective cohort study., Patients and Methods: 299 patients (age ≥ 60 years) who underwent bypasses in 1995-2006 were enrolled. Cognitive impairment was assessed by the Revised Hasegawa Dementia Scale, the Confusion Assessment Method was also used, and severity was graded as Grade I-III (mild to severe) based on the Delirium Rating Scale. All patients were followed for 3 years., Results: POD occurred in 88 patients (29%), with a median age of 75 (10) years (IQR). Onset was 2 (1) days postoperatively, and a duration of 2 (2) days was observed. POD was hyperactive in 89% and was Grade I, II, and III in 11%, 68%, and 21% respectively. Multiple logistic regression analysis identified the following risk factors for POD: age ≥ 72 years (<0.0001), end-stage renal failure (0.001), multiple occlusive lesions (<0.0001), cognitive impairment (0.003), and critical limb ischaemia (0.034). The 3-year survival rate was similar when comparing POD and non-POD patients (84% vs. 88%, NS)., Conclusions: This study identified 5 risk factors for POD in patients undergoing bypasses for limb ischaemia. Long-term outcomes were similar when comparing the patients who experienced POD with those who did not., (Copyright © 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-κB ligand (RANKL) in RA synoviocytes and CD4(+) T cells. We demonstrated MH7A cells, a human RA synovial cell line, and CD4(+) T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4(+) T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-α in MH7A cells and CD4(+) T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4(+) T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: The aim of the study is to determine factors affecting ischaemic wound healing and role of the angiosome concept in bypass surgery., Design: Single-centre, retrospective clinical study., Materials and Methods: A total of 249 consecutive critical ischaemic limbs with tissue loss in 228 patients who underwent distal bypasses from 2003 to 2009 were reviewed. A total of 81% of patients were diabetic, and 49% of patients had dialysis-dependent renal disease (end-stage renal disease, ESRD). Distal targets of bypasses were the crural artery (57%) and the pedal artery (43%)., Results: The complete healing of ischaemic wounds was achieved in 211 limbs (84.7%). ESRD (odds ratio (OR) 0.127, p < 0.001), diabetes (OR 0.216, p = 0.030), Rutherford category 6 (R6) with heel ulcer/gangrene (OR 0.134, p < 0.001), R6 except heel (OR 0.336, p = 0.025) and low albuminaemia (OR 0.387, p = 0.049) were negative predictors of wound healing. Regarding the angiosome, the healing rate in the indirect revascularisation (IR) group was slower than in the direct revascularisation (DR) group, especially in patients with ESRD (p < 0.001). However, the healing rates of the DR and IR groups were similar after minimising background differences with propensity score methods (p = 0.185)., Conclusions: In the field of bypass surgery, the angiosome concept seems unimportant, at least in non-ESRD cases. The location and extent of ischaemic wounds as well as co-morbidities may be more relevant than the angiosome in terms of wound healing., (Copyright © 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: We evaluated the mid-term outcome of distal venous arterialization (DVA) and the role of a combined free flap as a bridgehead for blood supply., Methods: In the past 5 years, nine patients with extensive tissue loss and lacking graftable distal arteries underwent DVA. These consisted of four primary DVAs, three combined DVA and free flap procedures, and two adjuvant DVAs for hemodynamically failed distal bypasses. After nine primary DVAs, three redo DVAs were performed for early failure. Etiologies were four Buerger disease and five arteriosclerosis obliterans, including three dialysis patients., Results: Among the nine DVA cases, there were five primary failures: two underwent amputation, two had successful redo DVA, and the remaining one did not require redo DVA. Primary patency, secondary patency, and limb salvage rates were 44.4%, 55.6%, and 77.8%, respectively. The postoperative period was 1-36 months (median 12). Angiography demonstrated DVA was effective in the early period, and development of collaterals or a capillary network from the free flap replaced the DVA function in the intermediate period., Conclusion: DVA can be effective as a procedure for limb salvage in patients without graftable distal arteries, and a combined free flap is effective and functions as a bridgehead for blood supply to the ischemic zone., (Copyright (c) 2010 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Embryonic stem (ES) cells maintain pluripotency by self-renewal. Several homeoproteins, including Oct3/4 and Nanog, are known to be key factors in maintaining the self-renewal capacity of ES cells. However, other genes required for the mechanisms underlying this process are still unclear. Here we report the identification by in silico analysis of a homeobox-containing gene, CrxOS, that is specifically expressed in murine ES cells and is essential for their self-renewal. ES cells mainly express the short isoform of endogenous CrxOS. Using a polyoma-based episomal expression system, we demonstrate that overexpression of the CrxOS short isoform is sufficient for maintaining the undifferentiated morphology of ES cells and stimulating their proliferation. Finally, using RNA interference, we show that CrxOS is essential for the self-renewal of ES cells, and provisionally identify foxD3 as a downstream target gene of CrxOS. To our knowledge, ours is the first delineation of the physiological role of CrxOS in ES cells.

Objective: To assess the effect of early vitrectomy for aggressive posterior retinopathy of prematurity (APROP) using fundus fluorescein angiography., Design: Retrospective, observational case series., Participants: Eleven eyes of 7 patients with APROP that underwent early vitreous surgery., Methods: All eyes underwent vitrectomy with lensectomy that removed the vitreous gel around the fibrovascular proliferative tissue, but not the proliferative tissue when fibrovascular proliferation and retinal detachment occurred despite retinal photocoagulation. Fundus fluorescein angiography was performed before and after the early vitreous surgery., Main Outcome Measures: Dye leakage from the fibrovascular tissue, dilation and tortuosity of the retinal vasculature, and shunt vessels were evaluated by fundus fluorescein angiography. The status of the retinal reattachment was assessed postoperatively., Results: Nine eyes had severe dye leakage from the fibrovascular tissue and 2 eyes had moderate leakage seen by preoperative fluorescein angiography. Severe dilation and tortuosity of the retinal vessels were detected in 10 eyes and shunt vessels in 7 eyes. Six to 12 days after successful surgery, the retina reattached and dilation and tortuosity of the retinal vessels decreased substantially. Dye leakage diminished markedly in all eyes, resolved completely in 7 eyes, and was still apparent slightly in 4. At the final examination, fibrovascular proliferation and retinal detachment did not progress in any eyes; however, 2 eyes had a dragged or folded retina. Follow-up ranged from 6 to 19 months (mean, 9.2)., Conclusions: Early vitrectomy that removes vitreous gel from around the proliferative tissue promptly reduces vascular activity and may limit progression of retinal detachment in APROP.

Purpose: To evaluate fluorescein angiography (FA) in eyes with aggressive posterior retinopathy of prematurity (AP-ROP)., Design: Retrospective, nonrandomized case series., Participants: Three patients (6 eyes) with AP-ROP., Methods: Three patients (6 eyes) diagnosed with AP-ROP during ROP screening between July 2007 and July 2008 were included in this study. Fundus photographs and FA were obtained before and after laser and surgical treatment using a wide-field digital pediatric imaging system., Main Outcome Measures: Fluorescein angiography and fundus photographs., Results: At the initial stage of AP-ROP, FA showed vascular abnormalities, including capillary nonperfusion throughout the vascularized retina, shunting in the vascularized retina, a circumferential demarcation line, and limited vessel development, which was difficult to identify only by ophthalmoscopy. After treatment, FA showed poorly developed retinal vessels, including 4 small major vessels without an arcade pattern, small macular vessels, an inhomogeneous capillary bed, and absence of a capillary-free zone in the fovea., Conclusions: Capillary bed loss throughout the vascularized posterior retina is characteristic of AP-ROP and may exacerbate retinopathy.

Mutations in the d-3-phosphoglycerate dehydrogenase (PHGDH; EC 1.1.1.95) gene, which encodes an enzyme involved in de novol-serine biosynthesis, are shown to cause human serine deficiency disorder. This disorder has been characterized by severe neurological symptoms including congenital microcephaly and psychomotor retardation. Our previous work demonstrated that targeted disruption of mouse Phgdh leads to a marked decrease in serine and glycine, severe growth retardation of the central nervous system, and lethality after embryonic day 13.5. To clarify how a serine deficiency causes neurodevelopmental defects, we characterized changes in metabolites, gene expression and morphological alterations in the spinal cord of Phgdh knockout mice. BeadChip microarray analysis revealed significant dysregulation of genes involved in the cell cycle. Ingenuity Pathway Analysis also revealed a significant perturbation of regulatory networks that operate in the cell cycle progression. Moreover, morphological examinations of the knockout spinal cord demonstrated a marked deficit in dorsal horn neurons. Radial glia cells, native neural stem/progenitor cells, accumulated in the dorsal ventricular zone, but they did not proceed to a G(0)-like quiescent state. The present integrative study provides in vivo evidence that normal cell cycle progression and subsequent neurogenesis of radial glia cells are severely impaired by serine deficiency.

Right-sided aortic arch accompanied by an aberrant origin of the left subclavian artery is rare and seen in 0.05% approximately 0.1% of the population. A 73-year-old woman with this anomaly was admitted to our institution because of the enlargement of the distal aortic arch aneurysm. She also had mild dysphagia. The size of the aneurysm was 70 mm in diameter and she underwent total arch replacement using selective cerebral perfusion through a median sternotomy. Additional right thoracotomy was not required and four cervical vessels were reconstructed. The postoperative course was uneventful. This case report shows median sternotomy alone may provide sufficient access for this pathology.

Objectives: To clarify the mechanism for poor patency of vein grafts after thrombectomy and the time limit for successful salvage operation, we investigated the time course of biologic degenerative changes in thrombosed vein grafts. Materials and methods The right femoral artery was replaced with a femoral vein graft in 25 mongrel dogs. After 3 months, grafts were explanted in 5 dogs (control grafts), and the remaining 20 dogs underwent femoral artery ligation to create a thrombosed graft. Of the 20 grafts, 5 were explanted at 3 days after ligation (group I-3) and 5 were explanted at 5 days after ligation (group I-5). Of the remaining 10 grafts, 5 underwent thrombectomy at 3 days after ligation (group II-3) and 5 underwent thrombectomy at 5 days after ligation, and were reimplanted into the left femoral artery, then explanted 28 days after reimplantation. The grafts were assessed with immunohistochemistry and prostaglandin (PG) I(2) assay (6-keto-PGI(1alpha))., Results: Of the 25 grafts, occlusion recurred in 3 in group II-5 within 28 days after reimplantation. There were significant differences between group I-5 and group I-3 or control grafts for percentage of areas positive for alpha-actin, total number of cells per field, and proliferating cell nuclear antigen (PCNA)-positive cells in layer of thickened intima and atrophied media (I/M), and for total cell and PCNA- positive cell numbers per field in the adventitia. Mean 6-ketoPGF(1alpha) was 40 +/- 14.1 pg/mg/min in control dogs, 84 +/- 18.9 pg/mg/min in group I-3, and 15.4 +/- 7.7 pg/mg/min in group I-5, demonstrating a significant reduction in group I-5 (P =.009)., Conclusion: Graft wall cell viability and PGI(2) production in thrombosed vein grafts are well preserved for up to 3 days. Therefore graft salvage operations no later than 3 days after thrombotic occlusion may provide acceptable long-term patency of salvaged grafts.

Objectives: This study investigated whether myocardial infarction patients with diabetes mellitus had lower heart rate reserve to exercise by measuring the increment in heart rate (HR) divided by the increment of norepinephrine (NE) concentration from rest to peak exercise (delta HR/log delta NE). The difference in exercise training effects was also investigated., Methods: The 148 patients after myocardial infarction were divided into two groups, the DM group (n = 34) and the non-DM group (n = 114). Cardiopulmonary exercise testing was performed in each subject at 1 and 3 months after the onset. Blood samples were taken at rest and immediately after peak exercise, rest brain natriuretic peptide, rest and peak norepinephrine were analyzed. Exercise training was performed from 1 to 3 months after the onset., Results: Resting heart rates were significantly higher in the DM group than in the non-DM group both at 1 and 3 months although peak heart rates were not significantly different. Peak oxygen uptake were lower in the DM group both at 1 and 3 months after onset of myocardial infarction compared to the non-DM group. End-tidal carbon dioxide pressure was lower and the rate of increase of minute ventilation to carbon dioxide output was higher in the DM group. Plasma brain natriuretic peptide was higher in the DM group. delta HR/log delta NE was 19.4 +/- 4.0 in the DM group and 22.2 +/- 5.6 in the non-DM group (p < 0.01), and increased in only the non-DM group. delta HR/log delta NE was more closely correlated with peak oxygen uptake in the DM group than in the non-DM group., Conclusions: Impaired response to exercise training may be caused, in part, by impaired heart rate reserve to exercise in patients with diabetes mellitus.

Purpose: Porcelain aorta is an indication for axillofemoral bypass. However, the procedure has definitive flaws. We present a new method for achievement of aortofemoral bypass., Methods: The portion of the distal aorta for anastomosis is wrapped with a double polytetrafluoroethylene mesh and fixed to the adventitia with continuous sutures. The adventitia of the anastomotic site is cut over the mesh until the calcified surface is disclosed. Margins of the mesh and the peeled adventitia are fixed along the anastomotic margin with continuous sutures. After the aorta and distal arteries are occluded with balloon catheters, an opening on the bared calcification is made with an airdrill and enlarged with a laminectomy rongeur. The anastomosis is performed between a graft and the mesh-reinforced adventitia with continuous sutures. Over 6 years, this method has been applied to nine patients with porcelain aorta who are diabetic or undergoing dialysis. The indications were disabling claudication in three patients and limb salvage in six patients., Results: No anastomotic complications or operative deaths were seen, and satisfactory mid-term results were obtained, with follow-up ranging from 3 to 62 months after surgery. One patient died of coronary heart disease 3 years after surgery, but the grafts retained a good function., Conclusion: This method is safe and effective, and more liberal application of this method may help improve outcome and quality of life.

Objective: Efficacy and duration of antibacterial activity of rifampicin-gelatin grafts against virulent organisms were evaluated in an animal model., Materials and Methods: Rifampicin-gelatin grafts were prepared with impregnation of Gelseal (Vascutek Ltd, Scotland) graft in 1 mg/mL rifampicin solution. Rifampicin-gelatin grafts (6 cm long; n = 24) and plain Gelseal grafts as controls (n = 4) were implanted into the canine abdominal aorta with inoculation of Staphylococcus epidermidis, Escherichia coli, or methicillin-resistant Staphylococcus aureus (MRSA), and the rifampicin-gelatin grafts were retrieved after 1 to 4 weeks. Disks cut from the retrieved rifampicin-gelatin grafts were placed on agar plates streaked with one of the organisms, and the graft antibacterial activity was assessed with the width of the inhibition zone., Results: In in vitro tests, initial inhibition zones (inhibition zone of 24 hours after incubation) of rifampicin-gelatin grafts against S epidermidis, MRSA, and E coli were 40.0 +/- 0.3 mm, 36.0 +/- 0.2 mm, and 11.8 +/- 0.1 mm, respectively. In the implantation, S epidermidis -inoculated rifampicin-gelatin grafts had no findings of graft infection, and no colony growth was recognized on the plates streaked with the perigraft fluids. Initial inhibition zones of S epidermidis -inoculated rifampicin-gelatin grafts retrieved at 1 or 2 weeks were 20.1 +/- 1.1 mm and 7.6 +/- 1.0 mm, respectively. In E coli -inoculated and MRSA-inoculated rifampicin-gelatin grafts, all of the eight animals had perigraft abscess, and blood culture test results probed septicemia in five animals with patent grafts at death. Inhibition zones against E coli or MRSA were not formed on the plates streaked with the same organism, whereas initial inhibition zones of E coli -inoculated and MRSA-inoculated rifampicin-gelatin grafts on S epidermidis -streaked plates were 8.0 +/- 0.2 mm and 18.5 +/- 0.5 mm, respectively. In the MRSA group, however, recolonization of high minimal inhibitory concentration strains developed within the inhibition zones as early as 24 hours. Histologically, neither organisms nor inflammatory cells were found in S epidermidis -inoculated rifampicin-gelatin grafts and tissue ingrowth was recognized at 2 to 4 weeks, whereas E coli -inoculated and MRSA-inoculated rifampicin-gelatin grafts had aggressive neutrophil infiltration into the graft interstices, revealing establishment of uncontrollable graft infection., Conclusion: These results suggested that rifampicin-gelatin grafts are clearly valid for S epidermidis infection, whereas no efficacy was recognized against either MRSA or E coli graft infection because of early development of high minimal inhibitory concentration MRSA strains or poor susceptibility.

Purpose: Endothelial cells (ECs) are subjected to the physical forces induced by blood flow. The aim of this study was to directly compare the EC signaling pathway in response to cyclic strain and shear stress in cultured bovine aortic ECs., Materials and Methods: The ECs were seeded on flexible collagen I-coated silicone membranes to examine the effect of cyclic strain. The membranes were deformed with a 150-mm Hg vacuum at a rate of 60 cycle/min for up to 120 minutes. For a comparison of the effect of shear stress, ECs from the same batch as used in the strain experiments were seeded on collagen I-coated silicone sheets. The ECs were then subjected to 10 dyne/cm(2) shear with the use of a parallel flow chamber for up to 120 minutes. Activation of the mitogen- activated protein kinases was assessed by determining phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 with immunoblotting., Results: ERK, JNK, and p38 were activated by both cyclic strain and shear stress. Both cyclic strain and shear stress activated JNK with a similar temporal pattern and magnitude and a peak at 30 minutes. However, shear stress induced a more robust and rapid activation of ERK and p38, compared with cyclic strain., Conclusions: Our results indicate that different mechanical forces induced differential activation of mitogen-activated protein kinases. This suggests that there may be different mechanoreceptors in ECs to detect the different forces or alternative coupling pathways from a single receptor.