Influence of UGT2B7, CYP3A4, and OPRM1 Gene Polymorphisms on Transdermal Buprenorphine Pain Control in Patients with Critical Lower Limb Ischemia Awaiting Revascularization.

BACKGROUND: Pain control in critical limb ischemia (CLI) varies considerably between individuals. OBJECTIVE: To evaluate pharmacogenetically the response to transdermal buprenorphine (BUP-TTS) in patients with CLI who are awaiting revascularization. METHODS: One hundred and seven patients with CLI were treated with BUP-TTS. The following were analyzed: (1) pain perception (visual analog scale (VAS) before and 4 days after treatment) and (2) genetics: glucuronosyltransferase (UGT2B7), cytochrome (CYP3A4), and µ-opioid receptor (OPRM1) gene polymorphisms. RESULTS: Ninety-three patients completed the study. The VAS score by the fourth day of analgesia dropped from 6.82 to 3.38 (P < 0.05). The analgesic response to BUP-TTS was greater in men than in women (P = 0.019). Patients who were AA homozygotes for the CYP3A4 gene showed the best response to analgesic treatment (P = 0.003). The combination of the CYP3A4 gene with UGT2B7 or OPRM1 was favorable to the effect of the CYP3A4 gene (P = 0.045 and P = 0.026, respectively). The combination of UGT2B7 with OPRM1 was ineffective (P = 0.648). The 3 polymorphisms together had no effect on response to treatment (P = 0.461). CONCLUSIONS: BUP-TTS is efficacious in the control of pain in patients with CLI. The homozygous AA carriers of the CYP3A4 gene respond better to treatment with BUP-TTS.

Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant.

Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life-threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow-up of 33 months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25·7%) and 46 patients developed a life-threatening bleeding episode (9·4%). Pulmonary and gastrointestinal bleeding were the most common sites for life-threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III-IV acute graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life-threatening bleeding events. The overall survival at 3 years among patients without bleeding was 67·1% for only 17·1% for patients with life-threatening bleeding (P < 0·001). In conclusion, life-threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III-IV GVHD and TMA were associated with its development.

Monitoring the practice of vascular surgery: findings from a national registry (1996-2011).

BACKGROUND: The goal of this article is to present for the first time to the international community the detailed findings and outcomes of the Spanish Vascular Registry (SVR) after 16 years of experience. METHODS: We examined the nationwide registry promoted by the Spanish Society of Angiology and Vascular Surgery (1996-2011). The changes in vascular surgical activity in Spain during the period of study were examined. We evaluated the number of services, medical specialists, consultations, admissions, and operations that occurred in Spain. We also assessed the trends in therapeutic activity and the medical and social impact of vascular pathology. RESULTS: A mean of 60 centers (range = 32-83) participated in the SVR (79.3 % of the total). In the last year of the study period, 94.3 % centers (100 % of teaching centers) participated. The mean number of activities per hospital per year was 5,298 consultations, 2,625 vascular explorations, 630 hospital admissions (61 % elective and 31 % emergency), and 742 surgical procedures. A total of 29,289 carotid stenosis procedures had been registered over 16 years. Both carotid endarterectomy (CEA) and carotid artery stenting (CAS) procedures have increased in frequency over time. In 2011, CAS constituted 19.3 % of all carotid procedures. A total of 31,703 abdominal aortic aneurysm (AAA) operations were registered during the study period. Surgery for ruptured AAA remained stable over time. Since its appearance in the year 2000, endovascular treatment (EVAR) increased steadily over time. Currently, EVAR represents about half of all AAA surgery (50.2 %). The total rate of in-hospital operative deaths was 1.1 %, but in-hospital mortality for open arterial surgery was 4 %. Mortality has decreased of late. CONCLUSIONS: The SVR has enabled us to understand the development and implementation of vascular surgery throughout Spain and to note the increased healthcare activity and the better overall results obtained as a consequence.

Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients.

Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.

Validation of the Walking Impairment Questionnaire for Spanish patients.

BACKGROUND: The Walking Impairment Questionnaire (WIQ) is a short, easy to complete, disease-specific questionnaire to assess intermittent claudication. A Spanish version of the WIQ for Hispanic Americans has recently been validated in Texas, but it needs to be validated for European Spanish people. PATIENTS AND METHODS: After translation and cultural adaptation of the WIQ, 920 patients with intermittent claudication (ankle brachial index < 0.9) completed two questionnaires (Spanish version of the WIQ and European Quality of Life 5 Dimension [EQ-5D]). The validity of the WIQ was determined by correlating WIQ and EQ-5D. Test-retest reliability and internal consistency were determined using the intra-class correlation coefficient (ICC) and Cronbach's alpha, respectively. RESULTS: The three domains of the WIQ were moderately correlated with the EQ-5D health outcome (r = 0.54 to 0.60; p < 0.001). Test-retest reliabilities ranged from ICC = 0.89 to 0.91 and internal consistency (Cronbach's alpha = 0.92) was high. CONCLUSIONS: The Spanish version of the WIQ for European Spanish patients was valid and reproducible, suggesting that it could be used in Spanish patients with intermittent claudication.

New functions of C3G in platelet biology: Contribution to ischemia-induced angiogenesis, tumor metastasis and TPO clearance.

C3G is a Rap1 guanine nucleotide exchange factor that controls platelet activation, aggregation, and the release of α-granule content. Transgenic expression of C3G in platelets produces a net proangiogenic secretome through the retention of thrombospondin-1. In a physiological context, C3G also promotes megakaryocyte maturation and proplatelet formation, but without affecting mature platelet production. The aim of this work is to investigate whether C3G is involved in pathological megakaryopoiesis, as well as its specific role in platelet mediated angiogenesis and tumor metastasis. Using megakaryocyte-specific C3G knockout and transgenic mouse models, we found that both C3G overexpression and deletion promoted platelet-mediated angiogenesis, induced by tumor cell implantation or hindlimb ischemia, through differential release of proangiogenic and antiangiogenic factors. However, only C3G deletion resulted in a higher recruitment of hemangiocytes from the bone marrow. In addition, C3G null expression enhanced thrombopoietin (TPO)-induced platelet production, associated with reduced TPO plasma levels. Moreover, after 5-fluorouracil-induced platelet depletion and rebound, C3G knockout mice showed a defective return to homeostatic platelet levels, indicating impaired platelet turnover. Mechanistically, C3G promotes c-Mpl ubiquitination by inducing Src-mediated c-Cbl phosphorylation and participates in c-Mpl degradation via the proteasome and lysosome systems, affecting TPO internalization. We also unveiled a positive role of platelet C3G in tumor cell-induced platelet aggregation, which facilitated metastatic cell homing and adhesion. Overall, these findings revealed that C3G plays a crucial role in platelet-mediated angiogenesis and metastasis, as well as in platelet level modulation in response to pathogenic stimuli.

Abdominal aortic aneurysm and acute appendicitis: a case report and review of the literature.

BACKGROUND: Abdominal aortic aneurysm and acute appendicitis occur relatively frequently in elderly patients. However, the co-occurrence of the two pathologies is very rare and serious. CASE PRESENTATION: We present the case of an elderly Caucasian patient who was aware of having an abdominal aortic aneurysm but refused treatment and was subsequently admitted to the hospital's emergency department with acute abdominal symptoms. A computed tomography scan raised the possibility of complication due to the characteristics of the aneurysm. The patient then agreed to emergency surgery. Laparotomy revealed the existence of an acute perforated appendicitis with a significant abscess in the right iliac fossa and an uncomplicated aneurysm. Appendectomy was performed and the abscess drained. The postoperative period passed without complications, and the patient again refused surgery for the aneurysm, which due to its anatomical characteristics was not a candidate for standard endovascular treatment. CONCLUSIONS: In light of this experience, we review the literature about the relationship between abdominal aortic aneurysm and acute appendicitis.

Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in diabetic patients with critical limb ischemia with no possibility of revascularization: study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial).

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

Open and endovascular treatment for pseudoaneurysms of the superior mesenteric artery.

BACKGROUND: Pseudoaneurysms of the superior mesenteric artery are rare, and their natural history is characterized by their tendency to rupture, thereby leading to a high mortality rate. Compared with classic surgical techniques (open), in recent years the possibility of endovascular treatment has increased. RESULTS: We report the cases of two patients with a pseudoaneurysm of the superior mesenteric artery. Each case was successfully treated in a different way: open and endovascular surgery. CONCLUSION: Despite the advantages (less risk for the patient) and good results obtained with endovascular surgery, this cannot completely replace open surgery. The choice of the most appropriate therapeutic option for pseudoaneurysms of the superior mesenteric artery depends on the state of the patient and the characteristics of the lesion. Open and endovascular surgical techniques are complementary, not mutually exclusive, techniques.

Simple and complex carotid paragangliomas. Three decades of experience and literature review.

BACKGROUND: Carotid paragangliomas are rare tumors. They are usually unique, non-secreting, resectable, and benign. However, additional rare cases of complex tumors (bilateral, secretory, nonresectable, or malignant) complicate the management and final outcomes. METHODS: Records of paragangliomas from our hospital are reviewed. Criteria defining complex paragangliomas have been previously defined. These are compared with those of the simple group. RESULTS: Fifty patients, two groups: simple (n = 39) and complex (n = 11). The patients in the complex group were significantly younger (47.7 vs 63.8 years). Postoperative nerve complications (45.4% vs 6.3%) and mortality during follow-up (27.3% vs 0%) were significantly more common in the complex group. Vascular complications (0% vs 3.1%) and early mortality (0%) were similarly in both groups. CONCLUSIONS: Patients with complex carotid paragangliomas are heterogeneous. The former are younger, exhibit a high degree of diagnostic and therapeutic complexity, and have poorer morbidity and mortality. Surgical experience and interdisciplinary collaboration are essential.

Spontaneous rupture of a mechanical valve in a mitral position (On-X) with migration-embolization to aortic bifurcation from the perspective of the vascular surgeon.

We report on the case of spontaneous rupture of an On-X-pure pyrolytic carbon mechanical valve prosthesis implanted seven years earlier, in a mitral position, at our hospital. The patient was admitted with valvular dysfunction and acute pulmonary edema requiring emergency surgery (prosthesis replacement); the absence of a leaflet was confirmed intraoperatively. The patient presented severe respiratory failure, which prolonged the postoperative period. A CT scan showed that the migrated leaflet was located in the aortic bifurcation with no apparent arterial lesion. Four months later, once the patient had recovered, laparotomy and aortotomy were performed in order to retrieve the leaflet, which was found to have become included (neoendothelized) in the aortic wall without compromising the latter's integrity or obstructing the blood flow. A subsequent CT scan confirmed the persistence of the leaflet in its initial position. The literature review highlights two singular facts: 1) this is the second published case of the escape of a leaflet from an On-X prosthesis (the first patient died); 2) this is the first case in which a laparotomy was performed to retrieve the leaflet but finally a decision was made to leave it in situ. Seven months later, the patient remained asymptomatic.

Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial.

Patients with peripheral artery disease (PAD) are at a high risk not only for the classical cardiovascular (CV) outcomes (major adverse cardiovascular events; MACE) but also for vascular limb events (major adverse limb events; MALE). Therefore, a comprehensive approach for these patients should include both goals. However, the traditional antithrombotic approach with only antiplatelet agents (single or dual antiplatelet therapy) does not sufficiently reduce the risk of recurrent thrombotic events. Importantly, the underlying cause of atherosclerosis in patients with PAD implies both platelet activation and the initiation and promotion of coagulation cascade, in which Factor Xa plays a key role. Therefore, to reduce residual vascular risk, it is necessary to address both targets. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial that included patients with stable atherosclerotic vascular disease, the rivaroxaban plus aspirin strategy (versus aspirin) markedly reduced the risk of both CV and limb outcomes, and related complications, with a good safety profile. In fact, the net clinical benefit outcome composed of MACE; MALE, including major amputation, and fatal or critical organ bleeding was significantly reduced by 28% with the COMPASS strategy, (hazard ratio: 0.72; 95% confidence interval: 0.59-0.87). Therefore, the rivaroxaban plus aspirin approach provides comprehensive protection and should be considered for most patients with PAD at high risk of such events.

Residual risk reduction opportunities in patients with chronic coronary syndrome. Role of dual pathway inhibition.

INTRODUCTION: In this review, the role of the rivaroxaban-plus-aspirin approach (dual pathway inhibition - DPI) in patients with chronic coronary syndrome (CCS) and to perform practical recommendations about its use was updated. AREAS COVERED: The contents of this review were proposed in an expert meeting. To identify relevant articles, a systematic search of Medline/Embase was performed (to July 2019), using the key words 'rivaroxaban', 'vascular dose', 'COMPASS' and 'coronary artery disease' in the search strategy. EXPERT OPINION: Despite current antithrombotic strategies (single/dual antiplatelet therapy) have decreased rates of recurrent cardiovascular events among patients with CCS, residual risk remains unacceptably high. The COMPASS trial showed in CCS patients that compared with aspirin 100 mg rivaroxaban 2.5 mg bid plus aspirin 100 mg reduced the risk of major cardiac events, cardiovascular hospitalization and mortality, without an increase of intracranial or fatal bleedings. Importantly, residual risk with the rivaroxaban plus aspirin approach was lower than with different dual antiplatelet therapy regimens. The rivaroxaban plus aspirin strategy is of particular benefit in patients with CCS and high-risk cardiovascular feature (i.e. ≥2 vascular beds, heart failure, renal insufficiency, peripheral artery disease, previous stroke or diabetes) and should be considered in these populations.

Corrigendum: Cost-Effective, Safe, and Personalized Cell Therapy for Critical Limb Ischemia in Type 2 Diabetes Mellitus.

[This corrects the article DOI: 10.3389/fimmu.2019.01151.].

Femoral vein injury and transposition techniques: a new approach to venous reconstruction in the setting of trauma.

Femoral vein (FV) injury is infrequent but potentially serious. Venous repair is the procedure of choice and multiple technical options are performed. This article describes a novel venous reconstruction technique of transposition of the injured FV into the deep femoral vein (DFV) system. Two men, 26 years and 32 years old, were evaluated after suffering penetrating wounds to the inguinal region, resulting in proximal FV injuries. Both the patients were treated with a lateral venorraphy of the common FV and transposition of the FV to DFV (end-to-side anastomosis). Venous thrombectomy was not required; intravenous unfractionated heparin and local acting heparin were administered during surgery. Low molecular weight heparin therapy was routinely administered before intervention in combination with elastic compression stockings. Duplex ultrasound at 1 month and 6 months after the injury demonstrated patency and luminal integrity of the involved vein in both the patients. Clinical follow-up without duplex at 12 months and 18 months revealed no evidence of chronic venous insufficiency. In instances of penetrating injury to the proximal FV, transposition to the DFV represents a novel and effective alternative to establishing venous outflow from the extremity. This technique is relatively simple and presents good permeability in the medium term. However, possible and often tolerated ligation of penetrating FV injuries should be considered a last option.

Cost-Effective, Safe, and Personalized Cell Therapy for Critical Limb Ischemia in Type 2 Diabetes Mellitus.

Cell therapy is a progressively growing field that is rapidly moving from preclinical model development to clinical application. Outcomes obtained from clinical trials reveal the therapeutic potential of stem cell-based therapy to deal with unmet medical treatment needs for several disorders with no therapeutic options. Among adult stem cells, mesenchymal stem cells (MSCs) are the leading cell type used in advanced therapies for the treatment of autoimmune, inflammatory and vascular diseases. To date, the safety and feasibility of autologous MSC-based therapy has been established; however, their indiscriminate use has resulted in mixed outcomes in preclinical and clinical studies. While MSCs derived from diverse tissues share common properties depending on the type of clinical application, they markedly differ within clinical trials in terms of efficacy, resulting in many unanswered questions regarding the application of MSCs. Additionally, our experience in clinical trials related to critical limb ischemia pathology (CLI) shows that the therapeutic efficacy of these cells in different animal models has only been partially reproduced in humans through clinical trials. Therefore, it is crucial to develop new research to identify pitfalls, to optimize procedures and to clarify the repair mechanisms used by these cells, as well as to be able to offer a next generation of stem cell that can be routinely used in a cost-effective and safe manner in stem cell-based therapies targeting CLI.

Surgery of vagal paragangliomas: six patients and review of literature.

BACKGROUND AND AIMS: Vagal paragangliomas (VPs) represent a rare pathology in which surgery is usually recommended, but where experience is crucial to reduce the number of post-operative complications. In this study, we present our experience and a review of the literature. METHODS: Between 1991 and 2006 we have treated 42 patients with 50 paragangliomas of the head and neck (26 carotid, 18 jugular/tympanic and 6 vagal). Examination of the literature (Medline and non-indexed Spanish source) from the last 30 years has revealed 23 series that each reported more than three cases; reaching a total of 332 VPs. RESULTS: VPs are infrequent among paragangliomas of the head and neck (6/50) presenting clinical peculiarities such as multiple tumours, and malignant evolution. Within this current series, surgery was possible in all cases. Post-operative dysfunction in cranial nerves was frequent (the cranial X nerve was systematically sacrificed). There were no bronco-aspirations or mortalities. The literature review reveals similar results. CONCLUSION: To obtain the best results, it is important that the candidates for surgery be selected by experts within multidisciplinary groups.

The comparative abilities of propofol and sevoflurane to modulate inflammation and oxidative stress in the kidney after aortic cross-clamping.

BACKGROUND: Propofol has been reported to provide protection against ischemia-reperfusion injury. Nuclear transcription factor kappa B (NFkappaB) plays a key role in oxidative stress and the inflammatory response during ischemia-reperfusion. We compared the effect of propofol with sevoflurane on kidney NFkappaB expression and systemic inflammatory responses induced by aortic clamping. METHODS: Twenty piglets were divided into four groups: sham surgery group with propofol (group SP, n = 5); sham group with sevoflurane (group SS, n = 5); and suprarenal clamping for 30 min with aorta-aortic bypass under propofol (group CP, n = 5) or sevoflurane (group CS, n = 5) anesthesia. Propofol was administered at 4 mg x kg(-1) x h(-1) i.v. and sevoflurane given at 1.5% inspiratory concentration. Peripheral blood and kidney biopsies were taken before the start of surgery, 15 min after unclamping the aorta, 24, 48, 72 h, and 7 days after surgery. Plasma creatinine, myeloperoxidase, tumor necrosis factor-alpha, interleukin 1-beta; and kidney superoxide anion and superoxidase dismutase were measured. The expression of inducible nitric oxide synthase and renal tissue NFkappaB was measured using Western blotting. RESULTS: Compared with the CS group, animals in the CP group had lower concentrations of myeloperoxidase, tumor necrosis factor-alpha, interleukin 1beta, superoxide anion, superoxidase dismutase (P < 0.05) from 24 to 72 h after surgery and diminished NFkappaB expression and inducible nitric oxide synthase activity (P < 0.05) at 48 and 72 h after surgery, respectively. CONCLUSIONS: Compared with sevoflurane, propofol administration during suprarenal aortic clamping and unclamping led to modulation of markers of inflammation and decreased NFkappaB expression.