Ubiquitin binds the amyloid ß peptide and interferes with its clearance pathways.

Several lines of evidence point to a compromised proteostasis associated with a reduction of the Ubiquitin Proteasome System (UPS) activity in patients affected by Alzheimer's Disease (AD) and suggest that the amyloid ß peptide (Aß) is an important player in the game. Inspired also by many reports, underlining the presence of ubiquitin (Ub) in the amyloid plaques of AD brains, here we set out to test whether Ub may bind the Aß peptide and have any effect on its clearance pathways. By using an integrated array of MALDI-TOF/UPLC-HRMS, fluorescence, NMR, SPR, Microscale Thermophoresis (MST) and molecular dynamics studies, we consistently demonstrated that Aß40 binds Ub with a 1 : 1 stoichiometry and K d in the high micromolar range. In particular, we show that the N-terminal domain of the Aß peptide (through residues D1, E3 and R5) interacts with the C-terminal tail of Ub (involving residues K63 and E64), inducing the central region of Aß (14HQKLVFFAEDVGSNK28) to adopt a mixed α-helix/ß-turn structure. ELISA assays, carried out in neuroblastoma cell lysates, suggest that Aß competitively binds Ub also in the presence of the entire pool of cytosolic Ub binding proteins. Ub-bound Aß has a lower tendency to aggregate into amyloid-like fibrils and is more slowly degraded by the Insulin Degrading Enzyme (IDE). Finally, we observe that the water soluble fragment Aß1-16 significantly inhibits Ub chain growth reactions. These results evidence how the non-covalent interaction between Aß peptides and Ub may have relevant effects on the regulation of the upstream events of the UPS and pave the way to future in vivo studies addressing the role played by Aß peptide in the malfunction of proteome maintenance occurring in AD.

The impact of insurance company mandated compression stocking trial on rate of intervention in patients with symptomatic venous reflux disease.

OBJECTIVE: Insurance companies have criteria for a venous intervention to be a covered procedure, including symptoms, vein size, and a trial of conservative therapy with compression stockings. The goal of this study was to see the impact of such mandated stocking use on ultimate intervention. METHOD: A retrospective review was done of prospectively gathered data entered in the electronic medical record. Two-hundred consecutive new patients evaluated at our vein center were included. RESULTS: Forty-four of the 200 patients did not require any procedures and 39 patients had procedures scheduled for small or asymptomatic venous changes that did not meet insurance criteria. This left 117 patients with venous symptoms in whom evaluation concluded that a corrective procedure could be performed. These interventions included largely radiofrequency ablation and phlebectomy. Of these 117 patients, 48 had previously used compression stockings. In the remaining 69 patients, stockings were provided on the day of initial consultation and these 69 patients served as the subjects for this review. At three month follow up, one patient reported the stockings help enough that she did not want to pursue correction. Two patients had continued pain and were planning correction once other unrelated issues resolved. Three patients said they never wore the stockings. Sixty-one patients had procedures performed. The average length of stocking use in patients who chose corrective procedures was 103 days. One patient could not be reached. CONCLUSION: Of the patients that reported they used the stockings as prescribed, one chose chronic stocking therapy and 63 patients either had procedures or were planning procedures. Use of prescription stockings was effective in avoiding intervention in one of 64 cases (2%), despite an average trial of 103 days. These results cast doubt on the merits of the use of an insurance company mandated stocking trial.

Improving warfarin anticoagulation therapy in a community health system.

An internal chart review of warfarin patients revealed a 44 percent complication rate resulting in higher treatment costs, and identified patient noncompliance, access to monitoring, and insufficient patient education as contributing factors. A warfarin usage guideline was created to assist physicians with warfarin management and subsequently the Anticoagulation Center (ACC) was established. To date over 950 patients have been managed through the ACC with therapeutic international normalized ratios an average of 82 percent of the time. Fewer bleeds and treatment failures have occurred in the ACC group, and a patient satisfaction survey revealed that ACC patients were very satisfied with their care more often than non-ACC patients.

Marking progress through data tracking.

In July 1997, Provider ran an overview of the foundation for continuous quality improvement (CQI). The following CQI principles were discussed: listening to customers; focusing on the processes that produce outcomes for customers; and using data to make decisions. The July article covered the first two aspects of CQI. In this article, the third principle, using data to make decisions, will be explored in further detail.

Balloon angioplasty by vascular surgeons.

BACKGROUND: Endovascular treatment of arterial disease of the lower extremity is performed by radiologists, cardiologists, and some vascular surgeons. This retrospective review was performed to measure complications and success rates in patients with extensive occlusive disease treated by vascular surgeons. METHODS: Balloon angioplasties were performed on 336 vascular segments as a part of 239 lower extremity revascularization procedures in 200 patients between April 1990, and May 1996. Immediate technical success was determined by completion angiography, measurement of pressure gradients, or ankle brachial indices (ABI) within 30 days. Late technical success was determined by duplex imaging or ABI. Late clinical success was defined as relief of presenting symptoms. RESULTS: Indications for intervention included claudication (51%), limb threat (45%), and failing grafts (4%). Sixty-one percent of the endovascular procedures were performed open, and 39% were percutaneously performed. Stents were utilized at 17% of the angioplasty sites. Procedures involved angioplasty of multiple arterial sites in 117 cases (55%), angioplasty combined with open surgical bypass (endarterectomy or thrombectomy) in 65 cases (19%), and a combination of surgery with a second angioplasty in 43 (13%). Complications occurred in 9 cases (3%). There were 2 deaths within 30 days (0.5%). Immediate technical success was 93% (140 of 151) for all aortoiliac segments, 88% (75 of 85) for femoral segments, 92% (54 of 59) for popliteal, and 84% (21 of 25) for tibials. The late technical success was 81% (118 of 145) for aortoiliac segments, 67% (55 of 82) for femoral, 73% (41 of 56) for the popliteals, and 75% (18 of 24) for the tibial segments. CONCLUSIONS: These data demonstrate that balloon angioplasty can be performed effectively by vascular surgeons with a low complication rate in a population of patients where limb salvage was a significant indication for the procedure, and treatment often required the correction of multilevel disease.

Symptomatic carotid artery disease: current management recommendations.

Proper management of symptomatic carotid artery disease requires prompt diagnosis and therapy based on both the patient's symptoms and the nature of the carotid lesion. Duplex ultrasonography is the preferred diagnostic modality for evaluating symptomatic patients for the presence of a hemodynamically significant carotid lesion. Arteriography can confirm severe carotid stenosis or delineate a nonstenotic, ulcerated plaque before surgery. Antiplatelet and anticoagulant agents administered after transient ischemic attacks or completed stroke have shown questionable benefit in stroke reduction as an independent variable. Results of randomized clinical trials support the use of carotid endarterectomy for symptomatic patients with ipsilateral carotid stenosis greater than 70 percent. The operation should be performed for appropriate indications by surgeons whose perioperative morbidity and mortality rates meet established guidelines.

Effects of estrogen on vein grafts.

The effect of estrogen on veins was evaluated in vitro and in vivo in three species. 17 beta-estradiol did not significantly alter 3H-thymidine uptake in vitro in segments from either canine femoral or human saphenous veins. In vivo in a rabbit carotid vein graft model, 17 beta-estradiol administration did not affect the development of intimal hyperplasia but was associated with a higher rate of graft thrombosis. These data suggest that the effects of estrogen on veins differs from the effects reported in arteries. These differences were seen both in vitro in veins taken from their normal location and in vivo in veins placed in the arterial circulation.

Gadolinium-enhanced magnitude contrast MR angiography of popliteal and tibial arteries.

To evaluate the efficacy of gadopentetate dimeglumine in MR angiography of the lower extremities, a flow phantom, seven healthy volunteers, and seven patients with peripheral vascular disease were studied with a magnitude contrast (MC) technique. The combination of an MC rephase-dephase gradient-refocused-echo pulse sequence, a 40-cm-long transmit-receive coil, and intravenous administration of a bolus of gadopentetate dimeglumine improved MR angiographic quality in the phantom, volunteers, and patients. Gadolinium enhancement decreased deleterious saturation effects and improved images of the popliteal and tibioperoneal arteries in the volunteers and patients. However, in some cases, venous overlap, imaging artifacts, and suboptimal visualization of subtle lesions limited interpretation. The authors conclude that gadolinium enhancement combined with an MC subtraction pulse sequence appreciably improves MR angiography of lower extremity arteries.

Spontaneous rupture of an adventitial cyst of the popliteal artery: confirmation with MR imaging.

A case of spontaneous rupture of an adventitial cyst in the popliteal artery is reported. Axial magnetic resonance (MR) images demonstrated the decompressed cyst, and MR angiography was a useful noninvasive technique for confirming vascular patency after cyst rupture.

Late iliac artery aneurysms and occlusive disease after aortic tube grafts for abdominal aortic aneurysm repair. A 35-year experience.

Controversy continues over whether patients treated with straight Dacron aortic tube grafts for an abdominal aortic aneurysm remain at significant risk for subsequent development of iliac aneurysm or occlusive disease. To address this issue, the authors performed a population-based analysis of 432 patients who had an abdominal aortic aneurysm diagnosed between 1951 and 1984. Aneurysm repair was performed eventually in 206 patients (48%). To ascertain differences in late development of graft-related complications, iliac aneurysms, and arterial occlusions, the authors compared all tube-graft patients with similar numbers of bifurcated-graft patients matched for age and year of operation. In the tube-graft group, no subsequent clinically evident or autopsy-proven iliac aneurysms or iliac occlusive disease were noted. Over a mean follow-up of 6 years (range, 4 to 18 years), new aortic aneurysms occurred in the proximal aorta in both tube and bifurcated-graft patients (5.0% and 2.5%, respectively). In contrast the cumulative incidence of graft-related complications was higher with a bifurcated prosthesis (12.8%) compared with a straight graft (5.0%) (p = 0.15). These problems generally occurred 5 to 15 years postoperatively and emphasize the need for long-term graft surveillance. The authors conclude that straight tube-grafts for repair of abdominal aortic aneurysms provide excellent late patency with minimal risk of subsequent iliac aneurysm development.

Peptide inhibition of neointimal hyperplasia in vein grafts.

Angiopeptin, a novel synthetic octapeptide, was evaluated as a new approach toward the inhibition of neointimal hyperplasia in vein grafts. Male New Zealand white rabbits (n = 22) underwent carotid artery interposition bypass grafting with autologous reversed jugular vein. Nine rabbits were in the treatment group, and 13 were in the control group. The treatment group received angiopeptin 20 micrograms/kg/day by subcutaneous injection beginning 1 day before operation and continuing for 3 weeks until they were killed. At death the vein grafts were fixed in situ with 10% buffered formalyn at 80 mm Hg perfusion pressure. Histologic sections through each vein graft were analyzed by computerized morphometric analysis for area of neointimal hyperplasia (mm2). Neointimal hyperplasia in the control animals was 0.080 + 0.017 mm2 (mean + SEM), whereas neointimal hyperplasia in the group treated with angiopeptin was 0.022 + 0.006 mm2 (mean + SEM) (p = 0.02). This is the first time that peptide inhibition of neointimal hyperplasia has been demonstrated in vein grafts and may have significant implications for future use in vascular surgery.

Noninvasive evaluation of the swollen extremity: experiences with 190 lymphoscintigraphic examinations.

Lymphoscintigraphy (LS), performed with technetium 99m-labeled antimony trisulfide colloid (Cadema Medical Products, Inc., Middletown, N.Y.), was used as a noninvasive diagnostic examination to evaluate the lymphatic circulation in 190 extremities of 115 patients. Forty-six patients had primary lymphedema, 48 had secondary lymphedema, and 21 patients had other causes of limb swelling. To determine the value of LS in surgical decision making, preoperative and postoperative LS of 16 patients who underwent surgical repair of the lymphatic abnormality were studied separately. Semiquantitative evaluation of the lymphatic drainage and visual interpretation of the image patterns were reliable to differentiate lymphedema from edemas of other origin (sensitivity: 92%, specificity: 100%). Although certain image patterns were characteristic of either primary or secondary lymphedema, LS could not consistently differentiate between the two types. Episodes of cellulitis in lymphedema clearly delayed lymph transport. LS was helpful in patient selection and follow-up after lymphatic surgery, but it did not prove patency of lymphovenous anastomoses. It was diagnostic in the evaluation of lymphangiectasia and was used to document successful surgical treatment of reflux of chyle. LS is safe and reliable and has no side effects. It should replace contrast lymphangiography in the routine evaluation of the swollen extremity.

Abdominal aortic aneurysm surgery: the basic evaluation of cardiac risk.

The treatment of coronary artery disease (CAD) prior to abdominal aortic aneurysm (AAA) surgery has reduced the operative mortality, but there is no consensus regarding how best to detect CAD. In this study, 160 patients with AAA were divided into 4 groups according to Goldman's weighted risk factors. All patients were evaluated for CAD by clinical and laboratory methods, including stress electrocardiogram (ECG) and radionuclide studies, and monitored perioperatively with serial ECGs, measurements of serum enzymes, filling pressures, and cardiac output. No one died, but 3.7% had myocardial infarct, 2.5% had heart failure, and 8.1% had arrhythmias. Cardiac complications were rare in patients without clinically evident CAD and in those in Goldman's classes I and II. It appears that patients without clinically detectable CAD can be operated upon with a low risk if they are carefully evaluated and monitored.

Encircling endocardial ventriculotomy for refractory ischemic ventricular tachycardia. III. Effects on regional left ventricular function.

In order to assess the effects of the encircling endocardial ventriculotomy (EEV) on regional left ventricular function, we cannulated seven adult mongrel dogs for cardiopulmonary bypass. Two pairs of miniature pulse-transit transducers were placed in mid-myocardium of the left ventricle, one pair in a region that would later be encompassed by an EEV and the other pair in a region of remote normal myocardium. Pressure-dimension data were analyzed during vena caval occlusions (after volume loading) both on and off cardiopulmonary bypass and both before and after performance of an EEV. The EEV results in a significant decrease in diastolic compliance of the encompassed myocardium. No significant compliance changes occurred in the control regions of the same hearts. This change in regional diastolic compliance is partially responsible for a loss of systolic excursion within the EEV-encompassed region and may help to explain the severe left ventricular dysfunction that has been observed in some patients following an EEV.