A prison called me : a clients perspective of some of the emotional effects of living with dissociative identity disorder and how they can affect behaviour

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Role of inflammation and platelet activation in the adverse cardiovascular outcomes of patients undergoing surgery for critical limb ischaemia

Increased platelet activation and inflammation play a key role in atherothrombosis. Patients with peripheral arterial disease are at increased risk of adverse cardiovascular events, particularly at the time of surgery. We postulated that the increase in peri-operative cardiovascular events is mediated by increased platelet activation and inflammation. We hypothesized that peri-operative dual anti-platelet therapy would improve biomarkers of atherothrombosis without causing unacceptable bleeding in patients undergoing surgery for critical limb ischaemia (CLI). Prior to interventional study, I validated a sensitive flow cytometric technique for the reproducible assessment of in vivo platelet activation in patients with peripheral arterial disease. Thirty patients with stable claudication, attended on two occasions to permit within-day and between-day comparisons. A variety of platelet activation markers were compared to the gold standard of platelet–monocyte aggregation. Platelet-monocyte aggregation demonstrated comparable within-day (mean difference ± co-efficient of reproducibility; 0.9±15.4%) and between-day reproducibility (2.0±12.4%). Plateletmonocyte aggregates correlated well with other platelet activation markers (P selectin r=0.30; Platelet CD40L r=0.41; Platelet microparticles r=0.27; P≤0.026) and monocyte activation markers (monocyte CD40 r=0.27;monocyte CD11b r=0.47; P≤0.026). In a cross sectional study, I demonstrated that resting in vivo platelet activation and inflammation was increased in patients with CLI in comparison to healthy controls, patients with stable claudication and those undergoing treatment for acute coronary syndromes. In addition, platelet activation and inflammation throughout the peri-operative period was markedly increased in CLI patients compared with non-vascular patients undergoing arthroplasty, and exceeded the rise attributable to the stress of surgery itself. In a prospective double-blind randomised controlled trial, 108 patients undergoing infra-inguinal revascularisation or amputation for CLI were maintained on aspirin (75 mg daily) and randomised to clopidogrel (600 mg prior to surgery, and 75 mg daily for 3 days; n=50) or matched placebo (n=58). Peri-operative in vivo platelet activation and inflammation, cardiac-Troponin I (c-TnI) release and bleeding outcomes were recorded. Clopidogrel reduced markers of platelet activation and inflammation before surgery and throughout the post-operative period. Overall, there were 18 troponin-positive events (16.7%), with half of the troponin rises (9) occurring prior to surgery. Patients with postoperative elevations in c-Tn I had significantly greater levels of pre-operative platelet-monocyte aggregation, monocyte CD40, IL-6 and hsCRP. However, despite reducing platelet and inflammatory markers, clopidogrel did not have a direct effect on peri-operative c-Tn I. There was no increase in major life-threatening or minor bleeding, although blood transfusions and wound haematomas were significantly increased. Using sensitive and validated methodologies, I have provided a detailed examination of in vivo platelet activation and inflammation in high-risk vascular surgical patients. This approach has provided the first objective assessment of the risks and benefits of intensive peri-operative anti-platelet therapy in this patient group. Dual anti-platelet therapy reduced biomarkers of atherothrombosis without causing unacceptable bleeding. However, large-scale clinical trials would be required to confirm whether these reductions translate into improvements in clinical outcome

Perioperative platelet and monocyte activation in patients with critical limb ischemia

BackgroundPatients with critical limb ischemia (CLI) have a high rate of adverse cardiovascular events, particularly when undergoing surgery. We sought to determine the effect of surgery and vascular disease on platelet and monocyte activation in vivo in patients with CLI.MethodsAn observational, cross-sectional study was performed at a tertiary referral hospital in the southeast of Scotland. Platelet and monocyte activation were measured in whole blood in patients with CLI scheduled for infrainguinal bypass and compared with matched healthy controls, patients with chronic intermittent claudication, patients with acute myocardial infarction, and those undergoing arthroplasty (n = 30 per group). Platelet and monocyte activation were quantified using flow cytometric assessment of platelet-monocyte aggregation, platelet P-selectin expression, platelet-derived microparticles, and monocyte CD40 and CD11b expression.ResultsCompared with those with intermittent claudication, subjects with CLI had increased platelet-monocyte aggregates (41.7% ± 12.2% vs 32.6% ± 8.5%, respectively), platelet microparticles (178.7 ± 106.9 vs 116.9 ± 53.4), and monocyte CD40 expression (70.0% ± 12.2% vs 52.4% ± 15.2%; P < .001 for all). Indeed, these levels were equivalent (P-selectin, 4.4% ± 2.0% vs 4.9% ± 2.2%; P > .05) or higher (platelet-monocyte aggregation, 41.7% ± 12.2% vs 33.6% ± 7.0%; P < .05; platelet microparticles, 178.7 ± 106.9 vs 114.4 ± 55.0/μL; P < .05) than in patients with acute myocardial infarction. All platelet and monocyte activation markers remained elevated throughout the perioperative period in patients with CLI (P < .01) but not those undergoing arthroplasty.ConclusionsPatients undergoing surgery for CLI have the highest level of in vivo platelet and monocyte activation, and these persist throughout the perioperative period. Additional antiplatelet therapy may be of benefit in protecting vascular patients with more severe disease during this period of increased risk.Clinical RelevancePeripheral arterial disease is increasingly common and is associated with a significant risk of cardiovascular complications, especially at the time of surgery. Despite this, patients are poorly provided with evidence-based therapies such as antiplatelet and lipid-lowering medications. Platelets play a key role in the pathogenesis of atherothrombosis, with elevated levels of in vivo platelet activation prognostic of adverse clinical events. This study demonstrates, for the first time to our knowledge, significantly greater levels of platelet activation in patients with severe peripheral arterial disease compared with patients with acute myocardial infarction or patients undergoing other moderate- to high-risk surgical procedures. This further emphasizes the need for improved risk stratification and cardioprotection of this vulnerable group

Early Experience With a Novel Dissection-Specific Stent-Graft to Prevent Distal Stent-Graft-Induced New Entry Tears After Thoracic Endovascular Repair of Chronic Type B Aortic Dissections

Background: The aim was to report short and mid-term outcomes of a novel, investigational, dissection-specific stent-graft (DSSG), specifically designed to address the features of chronic type B aortic dissection (CTBAD) and reduce the risk of distal stent-graft-induced new entry tears (dSINE). Materials and Methods: A retrospective single center cohort study of all patients undergoing TEVAR with the DSSG for CTBAD from January 1, 2017 to January 31, 2020. The DSSG, which is a modified stent-graft based on the Cook Zenith Alpha Thoracic platform, has no proximal barbs, and a customized longer body length with substantial taper. The second and third distal Z-stents are sited internally to avoid any contact of the metal skeleton with the dissection membrane and have reduced radial force, while the most distal stent was removed creating a distal 30 mm unsupported Dacron graft. Results: Sixteen patients (13 males, 3 females) with a median age of 66 years (range 31-79 years) underwent elective TEVAR of CTBAD using the DSSG. Six patients (38%) had an underlying connective tissue disorder. The median tapering was 10 mm (range 4 mm-21 mm) and median length 270 mm (range 210-380 mm). Technical success was achieved in all but one case (96%). One patient died within 30 days, due to retrograde type A dissection with cardiac tamponade. The 30-day rate of stroke, spinal cord ischemia, and re-interventions was 0%. After median imaging follow-up time of 17 months (range 1-31 months), one patient developed a dSINE 4 months after the index procedure. After median survival follow-up of 23 months (range 2-35 months), one late death occurred due to traumatic brain injury, while no aortic-related death occurred during follow-up. Complete false lumen (FL) thrombosis was achieved in 9 patients while the remaining 6 showed partial FL thrombosis. No instances of diameter increase at the level of treated aortic segment were noted with serial measurements showing either stable (n = 7) or decreased (n = 8) maximal transverse diameter. Conclusions: Use of a novel DSSG with low radial force for TEVAR in the setting of CTBAD is safe and feasible. This early real-world experience shows promising mid-term effectiveness with low rates of dSINE or unplanned re-interventions and satisfactory aortic remodeling during follow-up. Longer follow-up is needed, however, before any firm conclusions can be drawn

In vivo mononuclear cell tracking using superparamagnetic particles of iron oxide: feasibility and safety in humans

Background: Cell therapy is an emerging and exciting novel treatment option for cardiovascular disease that relies on the delivery of functional cells to their target site. Monitoring and tracking cells to ensure tissue delivery and engraftment is a critical step in establishing clinical and therapeutic efficacy. The study aims were (1) to develop a Good Manufacturing Practice–compliant method of labeling competent peripheral blood mononuclear cells with superparamagnetic particles of iron oxide (SPIO), and (2) to evaluate its potential for magnetic resonance cell tracking in humans. Methods and Results: Peripheral blood mononuclear cells 1–5×109 were labeled with SPIO. SPIO-labeled cells had similar in vitro viability, migratory capacity, and pattern of cytokine release to unlabeled cells. After intramuscular administration, up to 108 SPIO-labeled cells were readily identifiable in vivo for at least 7 days using magnetic resonance imaging scanning. Using a phased-dosing study, we demonstrated that systemic delivery of up to 109 SPIO-labeled cells in humans is safe, and cells accumulating in the reticuloendothelial system were detectable on clinical magnetic resonance imaging. In a healthy volunteer model, a focus of cutaneous inflammation was induced in the thigh by intradermal injection of tuberculin. Intravenously delivered SPIO-labeled cells tracked to the inflamed skin and were detectable on magnetic resonance imaging. Prussian blue staining of skin biopsies confirmed iron-laden cells in the inflamed skin. Conclusions: Human peripheral blood mononuclear cells can be labeled with SPIO without affecting their viability or function. SPIO labeling for magnetic resonance cell tracking is a safe and feasible technique that has major potential for a range of cardiovascular applications including monitoring of cell therapies and tracking of inflammatory cells