Coordination between proteasome impairment and caspase activation leading to TAU pathology: neuroprotection by cAMP.

Neurofibrillary tangles (NFTs) are hallmarks of Alzheimer's disease (AD). The main component of NFTs is TAU, a highly soluble microtubule-associated protein. However, when TAU is cleaved at Asp421 by caspases it becomes prone to aggregation leading to NFTs. What triggers caspase activation resulting in TAU cleavage remains unclear. We investigated in rat cortical neurons a potential coordination between proteasome impairment and caspase activation. We demonstrate that upon proteasome inhibition, the early accumulation of detergent-soluble ubiquitinated (SUb) proteins paves the way to caspase activation and TAU pathology. This occurs with two drugs that inhibit the proteasome by different means: the product of inflammation prostaglandin J2 (PGJ2) and epoxomicin. Our results pinpoint a critical early event, that is, the buildup of SUb proteins that contributes to caspase activation, TAU cleavage, TAU/Ub-protein aggregation and neuronal death. Furthermore, to our knowledge, we are the first to demonstrate that elevating cAMP in neurons with dibutyryl-cAMP (db-cAMP) or the lipophilic peptide PACAP27 prevents/diminishes caspase activation, TAU cleavage and neuronal death induced by PGJ2, as long as these PGJ2-induced changes are moderate. db-cAMP also stimulated proteasomes, and mitigated proteasome inhibition induced by PGJ2. We propose that targeting cAMP/PKA to boost proteasome activity in a sustainable manner could offer an effective approach to avoid early accumulation of SUb proteins and later caspase activation, and TAU cleavage, possibly preventing/delaying AD neurodegeneration.

Unselected percutaneous access with large vessel closure for endovascular aortic surgery: experience and predictors of technical success.

INTRODUCTION: The effectiveness of percutaneous access with large vessel closure (pEVR) in non-selective groups of patients undergoing endovascular aneurysm repair (EVR) remains unclear. This study aims to identify factors that predict success in pEVR, performed using percutaneous access and the Prostar XL (Abbott Vascular, Redwood City, Calif) closure device. METHOD: Consecutive patients who underwent pEVR between April 2010 and March 2011 were identified from a prospectively maintained database. Procedural and postoperative outcomes were compared with consecutive patients who underwent endovascular aneurysm repair using standard open femoral access between April 2008 and March 2009. To determine the predictors of technical success of pEVR, the association between clinical, anatomical and procedural variables with technical success, were examined in a multiple logistic regression model. RESULTS: pEVR was attempted in 186 common femoral arteries (CFAs) with a technical success rate of 95.2% (177/186). Conventional open femoral access in the historic control group was performed in 208 CFAs. pEVR was associated with a reduced operation length (131 min [105-152] versus 150 min [124-195], p≤0.001) and length of stay (2 days [2-5] versus 4 days [2-7], p = 0.01) in patients undergoing infrarenal EVR. In secondary analysis of outcomes following percutaneous access in 91 CFAs, pre-operative renal failure, CFA depth (min and max), CFA diameter (min and max) and operator experience predicted success of percutaneous access in univariate analysis. Operator experience was the only independent predictor of technical success (p = 0.05) after adjustment for all confounding variables. CONCLUSION: pEVR using the Prostar XL device is effective in the majority of patients. In this study there were benefits in terms of reduced postoperative complications, shorter procedures and decreased lengths of stay. Operator experience is a predictor of technical success for pEVR, irrespective of clinical and morphological characteristics at baseline.

Post-operative surveillance after open peripheral arterial surgery.

BACKGROUND: Guidelines and protocols assist in the clinical management of patients, helping to utilise available resources efficiently, however, there is limited documented guidance on surveillance of patients following open arterial surgery. The frequency of clinical follow up, Doppler ultrasound measurements and radiological imaging should all be justified. Here we review the available literature to offer an evidenced based approach to postoperative care. METHOD: An electronic search was made of Medline and Embase databases through September 2009 revealing over 2300 studies in the initial searches. Following title and abstract screening, the relevant medical literature concerning post-operative surveillance of open vascular procedures was reviewed (300 papers). 42 papers were included in this review. Surveillance recommendations were constructed from the evidence presented. RESULTS AND CONCLUSION: Detailed anatomical imaging is available for the technical assessment in the majority of patients' postoperative management; however there is little Level 1 evidence to guide modality or timing. Grades B and C recommendations form the majority of surveillance recommendations. Clinical review remains the mainstay of surveillance following open peripheral arterial surgery. Duplex scanning is the imaging modality of choice when indicated in most instances. Minimal data exists to quantify quality of life or intervention efficacy.

Endovascular repair of an acute, mycotic, ascending aortic pseudoaneurysm.

This report describes endovascular stenting of an acute mycotic ascending aortic aneurysm. An eighty-three year old lady presented nine weeks after aortic valve surgery and subsequent thyroidectomy with sternal pain secondary to a mycotic ascending aortic pseudoaneurysm. The pseudoaneurysm was visible through the unhealed sternum. Open repair was considered too high a mortality risk. Endovascular stenting was performed using two covered infrarenal proximal extension devices (GORE Excluder Aortic Extender(®), W. L. Gore & Associates, Flagstaff, Arizona, USA) deployed from a right axillary approach utilising overdrive cardiac pacing. Post procedure imaging revealed shrinkage of the pseudoaneurysm sac.

Randomized clinical trial of VNUS ClosureFAST radiofrequency ablation versus laser for varicose veins.

BACKGROUND: Endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) are both associated with excellent technical, clinical and patient-reported outcomes for the treatment of varicose veins. The aim of this study was to compare the techniques in a randomized clinical trial. METHODS: Consecutive patients with primary great saphenous vein reflux were randomized to EVLA (980 nm) or RFA (VNUS ClosureFAST) at a single centre. The primary outcome measure was postprocedural pain after 3 days. Secondary outcome measures were quality of life at 6 weeks, determined by the Aberdeen Varicose Vein Questionnaire (AVVQ) and Short Form 12 (SF-12), and clinical improvement assessed by the Venous Clinical Severity Score (VCSS). Analyses were performed on the basis of intention to treat using multivariable linear regression. RESULTS: Some 131 patients were randomized to EVLA (64 patients) or RFA (67). Mean(s.d.) pain scores over 3 days were 26.4(22.1) mm for RFA and 36.8(22.5) mm for EVLA (P = 0.010). Over 10 days, mean(s.d.) pain scores were 22.0(19.8) mm versus 34.3(21.1) mm for RFA and EVLA respectively (P = 0.001). The mean(s.d.) number of analgesic tablets used was lower for RFA than for EVLA over 3 days (8.8(9.5) versus 14.2(10.7); P = 0.003) and 10 days (20.4(22.6) versus 35.9(29.4) respectively; P = 0.001). Changes in AVVQ, SF-12 and VCSS scores at 6 weeks were similar in the two groups: AVVQ (P = 0.887), VCSS (P = 0.993), SF-12 physical component score (P = 0.276) and mental component score (P = 0.449). CONCLUSION: RFA using VNUS ClosureFAST was associated with less postprocedural pain than EVLA. However, clinical and quality-of-life improvements were similar after 6 weeks for the two treatments.

Purinergic modulation of human corpus cavernosum relaxation.

The activation of P2Y(6) receptors has been previously reported to cause vascular smooth muscle constriction and relaxation. The aim of our study was to determine the effect of P2Y(6) receptor subtype activation on human cavernosal function. Cavernosal tissue was obtained from 23 patients undergoing gender reassignment surgery. Immunohistochemistry (IHC) and Western blotting were used to determine the presence of P2Y(6) receptors in corpus cavernosal tissue. The effects of UDP (a selective P2Y(6) receptor agonist) before and after the addition of distilled water (control), cibacron blue 3GA (CB, a P2Y(6) receptor antagonist; 10(-4) m) or N-nitro-L-arginine methyl esther (L-NAME, a NO synthase inhibitor; 10(-4) m) were assessed on phenylephrine (PE; 10(-4) m) pre-contracted cavernosal strips using organ baths. Electrical field stimulation (EFS; 0.5-32 Hz) was performed in the absence and presence of CB to determine neuronal-mediated P2Y(6) receptor responses. IHC and Western blotting revealed the presence of P2Y(6) receptors on cavernosal sections. UDP at 10(-4) m and 10(-3) m induced a 5% and 16% relaxation of the PE-mediated response (both p < 0.0001), respectively, which was significantly blocked by CB (48% reduction of the UDP 10(-3) m response, p < 0.002) but not affected by L-NAME. EFS-induced relaxations of pre-contraction strips were not significantly altered by CB. We have found the presence of P2Y(6) receptors in human cavernosal tissues, that when activated induce cavernosal smooth muscle cell relaxation via non-neuronal and non-nitric oxide dependent mechanism. Further investigation is needed to establish whether P2Y(6) receptors play a physiological role in penile erection.

Blood oxygen level-dependent (BOLD) magnetic resonance imaging in patients with dypiridamole induced ischaemia; a PET comparative study.

BACKGROUND: Blood oxygen level-dependent (BOLD) MRI relies on changes in deoxyhaemoglobin level in tissues under stress for signal variation and may be used for detection of ischaemic myocardium. METHODS: 15 patients with stress induced myocardial ischaemia on PET scanning underwent rest and dypiridamole stress MRI using a double breath-hold T2-weighted, ECG gated sequence to produce BOLD contrast images and cine-MRI for wall thickening assessment. Signal change on BOLD MRI and wall thickening were compared between rest and stress images in ischaemic and non-ischaemic myocardial segments. RESULTS: Using PET, 156 segments were identified with reversible ischaemia and 324 as non-ischaemic. The ischaemic segments were found on BOLD MRI to have an average signal change between rest and stress of -16.7% compared to -14% in the non-ischaemic segments (p=0.04). The average wall thickening was 7.8 mm in the ischaemic segments compared with 9.5 mm in the non-ischaemic segments (p<0.0001). CONCLUSION: BOLD MRI with wall thickening assessment may differentiate ischaemic from non-ischaemic myocardium in patients with stress induced myocardial ischaemia. Larger studies with improved spatial resolution would help define a threshold for detection of ischaemia as well as determine this technique's sensitivity and specificity.

Alterations in purinoceptor expression in human long saphenous vein during varicose disease.

OBJECTIVES: Varicose veins are dilated tortuous veins of varying tone. Purinergic signalling is important in the control of tone and in mediating trophic changes in blood vessels. The expression of P2 receptors in control and varicose veins will be examined. METHODS: Purinergic signalling in circular and longitudinal smooth muscle of the human long saphenous vein was studied in control and varicose tissues using immunohistochemistry, organ bath pharmacology and electron microscopy. RESULTS: P2X1, P2Y1, P2Y2, P2Y4 and P2Y6 receptors were present on circular and longitudinal smooth muscle. Purine-mediated circular and longitudinal muscle contractions were weaker in varicose veins. Electron microscopy and immunohistochemistry findings support the view that smooth muscle cells change from the contractile to synthetic phenotype in varicose veins, associated with an upregulation of P2Y1 and P2Y2 receptors and a down regulation of P2X1 receptors. CONCLUSIONS: Down regulation of P2X1 receptors on the smooth muscle of varicose veins is associated with loss of contractile activity. Upregulation of P2Y1 and P2Y2 receptors is associated with a shift from contractile to synthetic and/or proliferative roles. The phenotype change in smooth muscle is associated with weakening of vein walls and may be a causal factor in the development of varicose veins.

Sinus of Valsalva fistula with quadricuspid aortic valve, a first reported association.

Quadricuspid aortic valve and sinus of Valsalva fistula are rare congenital anomalies. We report the first case of association of these two congenital anomalies in an adult patient and the important role of Magnetic Resonance Imaging (MRI) in establishing and confirming the correct diagnosis and helping in planning the treatment.

Benign complications of expandable metal stents used in the palliation of oesophageal carcinoma: two case reports.

We describe two patients who were treated with self-expanding metal stent (SEMS) insertion as palliation of malignant oesophageal strictures. Both patients re-presented with dysphagia several months after SEMS insertion due to benign strictures. Initial treatment with balloon dilation and medical management had limited success so both patients had further SEMS inserted across the secondary benign strictures. This provided very good symptomatic relief. Chemotherapy and chemo-radiation in patients with inoperable oesophageal carcinoma are prolonging patient survival. As patients survival lengthens benign complications of SEMS may become an increasing clinical problem.

Automatic detection of coronary artery disease in myocardial perfusion SPECT using image registration and voxel to voxel statistical comparisons.

The purpose of this study was to compare the performance of automatic detection of coronary artery disease (CAD) with that of expert observers. A male and female normal image template was constructed from normal stress technetium-99m single photon emission computed tomography (SPECT) studies. Mean and standard deviation images for each sex were created by registering normal studies to a standard shape and position. The test group consisted of 104 patients who had been routinely referred for SPECT and angiography. The gold standard for CAD was defined by angiography. The test group studies were registered to the respective templates and the Z-score was calculated for each voxel. Voxels with a Z-score greater than 5 indicated the presence of CAD. The performance of this method and that of three observers were compared by continuous receiver operating characteristic (CROC) analysis. The overall sensitivity and specificity for automatic detection were 73% and 92%, respectively. The area (Az) under the CROC curve (+/-1 SE) for automatic detection of CAD was 0.88+/-0.06. There was no statistically significant difference between the performances of the three observers in terms of Az and that of automatic detection (P> or =0.25, univariate Z-score test). The use of this automated statistical mapping approach shows a performance comparable with experienced observers, but avoids inter-observer and intra-observer variability.

Effects of warfarin therapy on plasma fibrinogen, von Willebrand factor, and fibrin D-dimer in left ventricular dysfunction secondary to coronary artery disease with and without aneurysms.

Cardiac impairment in patients is associated with intracardiac thrombus formation and thromboembolism. A high prothrombotic state may exist in such patients, and abnormalities in plasma markers of thrombogenesis may be indicative of such a state. The aim of this study was to determine the associations of left ventricular (LV) aneurysm formation and dysfunction with plasma fibrinogen, von Willebrand factor, and fibrin D-dimer, which are markers associated with thrombus formation (thrombogenesis) and to investigate the effects of warfarin given to patients with LV aneurysms on fibrinogen and D-dimer levels. A cross-sectional study of 112 patients with coronary artery disease was initially performed: 34 patients had normal LV function (group 1); 30 had LV dysfunction without aneurysm formation (group 2); 29 had LV aneurysms without anticoagulation (group 3a); and 19 patients had LV aneurysms with warfarin therapy (group 3b). Results were compared with 158 population controls from a random population sample. A longitudinal study of 10 patients given warfarin was also performed. In group 1, plasma fibrinogen (median difference 0.36 g/L; p = 0.0009) and von Willebrand factor (median difference 17 IU/dl; p = 0.04) were elevated, whereas plasma D-dimer levels (median difference 23.0 ng/ml; p = 0.001) were lower than those in population control subjects. There were no significant differences in plasma fibrinogen, von Willebrand factor, or D-dimer levels between groups 1 and 2. In group 3a, plasma fibrinogen was elevated when compared with group 1 (median difference 0.6 g/L; p = 0.0001), with a trend toward high von Willebrand factor levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective measurement of changes in regional wall motion characteristics following coronary artery bypass grafting using tomographic radionuclide ventriculography.

Difficulties arise when using non-invasive methods to measure changes in regional left ventricular function. With the increasing recognition of the entity of hibernating myocardium, and the known asymmetric effects of coronary artery disease, this is an important problem, as it prevents detailed investigation of the effects of revascularization upon ventricular function. We investigated the use of tomographic radionuclide ventriculography in assessing such changes. Twenty consecutive patients (18 males, 2 females, mean age 60 years), undergoing elective coronary artery bypass surgery, were identified and imaged prior to and after surgery. The mean global left ventricular ejection fraction was 42 and 45% pre- and post-surgery, respectively. Following revascularization, it was improved in 9 patients, unchanged in 3 and deteriorated in 8. By comparison with pooled normal data from 25 subjects, 10 patients were noted to have overall resting phase values within normal limits. After surgery, an improvement was seen in 5 patients, no significant change in 11 and a deterioration in 4. With respect to regional ejection fraction, 24 of 80 segments improved, 25 remained unchanged and 31 deteriorated. For regional phase analysis, 26 improved, 45 remained unchanged and 9 deteriorated. confirmed that important regional changes in left ventricular function occur following revascularization, even without a change in global ejection fraction.

Is diastolic dysfunction associated with thrombogenesis? A study of circulating markers of a prothrombotic state in patients with coronary artery disease.

Clinical data on the contributory role of heart failure to thromboembolic risk does not differentiate between systolic and diastolic left ventricular dysfunction. We therefore conducted a population-controlled cross-sectional study to determine levels of plasma fibrinogen (associated with thromboembolism), fibrin D-dimer (a marker of fibrin turnover) and von Willebrand factor (a marker of endothelial dysfunction) in patients with ischaemic heart disease (a common cause of diastolic dysfunction) in whom left ventricular diastolic function was defined by echocardiography. We studied 106 patients: those with normal left ventricular function (n = 42, Group 1); those with left ventricular dysfunction but without aneurysms (n = 34, Group 2); and those with left ventricular aneurysm formation (n = 30, Group 3). Each of these groups was subdivided into those with (a) and without (b) diastolic dysfunction. Diastolic dysfunction was present in over 60% of patients, irrespective of left ventricular systolic impairment. There were no significant differences in median levels of plasma fibrinogen, fibrin D-dimer or von Willebrand factor in each group of patients with ischaemic heart disease, whether or not left ventricular diastolic dysfunction was present (Mann-Whitney test; P = N.S.). Systolic (rather than diastolic) dysfunction was the main correlate of these (analysis of variance, general linear model--ANOVA-GLM--P < 0.05) and the greatest abnormalities of fibrinogen, endothelial dysfunction and intravascular fibrin turnover were seen in patients with left ventricular aneurysms whether or not diastolic dysfunction was present. This study demonstrates that there is no evidence of a significant additional contribution to thrombotic risk (as assessed by plasma fibrinogen, von Willebrand factor and fibrin D-dimer) for patients with left ventricular diastolic dysfunction. A relationship is noted between some prothrombotic factors and Doppler indices of flow, which suggests a possible association between cardiac haemodynamics and thrombogenesis.

Do radionuclide and echocardiographic techniques give a universal cut off value for left ventricular ejection fraction that can be used to select patients for treatment with ACE inhibitors after myocardial infarction?

OBJECTIVE: To determine whether echocardiography and radionuclide angiography give comparable results when the left ventricular ejection fraction is measured early after myocardial infarction and thus whether, irrespective of the method used, a single value for the ejection fraction could be used as a guide for starting treatment with an angiotensin converting enzyme inhibitor. DESIGN: Prospective comparison of measurement of left ventricular ejection fraction by echocardiography and radionuclide angiography. SETTING: Coronary care units of two university teaching hospitals in Glasgow. PATIENTS: 99 patients studied within 36 hours of acute myocardial infarction. OUTCOME MEASURES: Left ventricular ejection fraction assessed by echocardiography and radionuclide angiography. RESULTS: 70 (77%) of the 99 patients had ejection fraction measured by both echocardiographic and radionuclide techniques, 30 in centre 1 and 40 in centre 2. In centre 1 the mean difference (SD) in ejection fraction (radionuclide angiography--echocardiography) was -8 (10%); 95% CI -12 to -4%. In centre 2 the mean difference was -14 (11%); 95% CI -17 to -11%. If patients had been treated with an ACE inhibitor on the basis of a radionuclide ejection fraction of < 40% then 93% in centre 1 (28 of 30) and 98% in centre 2 (39 of 40) would have been treated. This compares with 63% (19 of 30) and 50% (20 of 40), respectively if echocardiography had been used as a guide. CONCLUSION: Measurement of ejection fraction is highly dependent on the method used and it is therefore impossible to quote a universally applicable figure for left ventricular ejection fraction below which an ACE inhibitor should be used after myocardial infarction.