Tau self-association: stabilization with a chemical cross-linker and modulation by phosphorylation and oxidation state

tau is a major component of paired helical filaments found in the neurofibrillary tangles of Alzheimer's diseased brain. However, the mechanism or mechanisms responsible for the association of tau to form these aggregates remains unknown. In this study, the role of intermolecular disulfide bonds in the formation of higher order oligomers of bovine tau and the human recombinant tau isoform T3 was examined using the chemical cross-linking agent disuccinimidylsuberate (DSS). In addition, the role of phosphorylation and oxidation state on the in vitro self-association of tau was studied using this experimental model. Stabilization of tau-tau interactions with DSS indicated that intermolecular disulfide bonds probably play a predominant role in dimer formation, but the formation of higher order oligomers of tau cannot be attributed to these bonds alone. tau-tau interactions were significantly decreased either by blocking Cys residues or by exposing the tau to a reducing (nitrogen and dithiothreitol), instead of an oxidizing, environment. tau self-association was also significantly decreased by prior phosphorylation with calcium/calmodulin-dependent protein kinase II. Phosphorylation by cyclic AMP-dependent protein kinase or dephosphorylation by alkaline phosphatase did not alter tau self-assembly. These data suggest a role for several factors that may modulate tau self-association in vivo.     

Is it possible to perform immediate cardiac assist using untrained latissimus dorsi muscle in a work-rest regimen?

The authors investigated what contractile force (CF) could be obtained from unconditioned latissimus dorsi muscle immediately after mobilization and for the 2 week vascular period of recovery. Latissimus dorsi muscle mobilization was performed on seven adult (4 experimental and 3 control) sheep leaving only the pedicle and the peripheral muscle intact. Telectronics stimulators (Myostim 7220; Teletronics Pacing Systems, Inc, Englewood, CO) were implanted. Immediately after mobilization 11-35% of the initial CF was lost. A 30 min fatigue test was performed 1 hr after mobilization (20 g/kg preload, 10 V, 10 Hz, 15 BPM, 6 impulses per burst) using a 1 min work-1 min rest regimen. Two sheep lost 2-12% of initial CF; two increased CF by 14-24%. At the end of the fatigue test, CF consisted of 74-89% of immobilized CF. Electrical stimulation training of the muscle was then initiated with the following regimen in the experimental animals only: 15 BPM, single impulses, 5 V, 10 Hz. Every day the muscle was exercised using a work-rest regimen to mimic cardiac assist, starting with 20 min on day 2, and increasing by 2 min per day until a total of 50 min was reached on day 16. All animals were retested for CF using a 42 min fatigue test on days 6, 11, and 16. On day 6, there was no fatigue evident in the experimental group during the 42 min test. CF after testing was 59-81% (mean 67%) of initial data. In the control group (animals with no electrical stimulation training protocol), CF decreased by 11% (from 64 to 53%). On day 11, there was no fatigue evident in the experimental group; CF in all animals increased by 2-8%. On day 16, there was also no fatigue evident in the experimental group; CF increased by 0-9%. An additional 20 min of continuous contraction (15 BPM) fatigue testing was performed on the muscle without rest between the tests. No fatigue was evident at the end of testing. Light microscopic analysis of latissimus dorsi muscle biopsy specimens taken on the days of testing showed no evidence of necrotic damage. Our investigations suggest that it may be possible to start muscle transformation immediately after mobilization and use the untrained latissimus dorsi muscle for cardiac assist immediately after surgery for short periods.     

Use of exercise technetium-99m sestamibi SPECT imaging to detect residual ischemia and for risk stratification after acute myocardial infarction

The clinical presentation, electrocardiographic findings, and technetium-99m sestamibi single-photon emission computed tomography (SPECT) imaging results of 134 consecutive patients who underwent nuclear exercise testing within 14 days of an acute myocardial infarction (AMI) were correlated with cardiac events over a 15 +/- 10-month follow-up. Whereas only 23 patients (17%) had chest pain and 31 (23%) had ischemic ST-segment depression during exercise, 94 (70%) had ischemia on SPECT (p < 0.001). On follow-up, 13 patients experienced a cardiac event: 7 were rehospitalized for unstable angina, 3 had recurrent AMI, and 3 died of cardiac causes. Ischemia on the sestamibi images identified 11 of these patients (85%), whereas chest pain identified only 3 (23%, p = 0.006), and electrocardiographic ischemia identified only 4 (31%, p = 0.017). The presence of either ischemia as seen on SPECT or defects in multiple vascular territories identified 12 patients (92%) with an event, including all who had cardiac death. By Cox regression analysis of clinical, stress, and image parameters, the number of ischemic defects on SPECT was the only significant correlate of a future event (chi-square = 4.62, p = 0.03), and patients with > or = 3 reversible sestamibi defects had an event rate of 38%. The extent of ischemia as seen on nuclear imaging remained a strong correlate (p = 0.008) of an event in the 54 patients (40%) who had received thrombolytic therapy. Thus, exercise technetium-99m sestamibi SPECT after AMI frequently reveals residual ischemia, and is better than clinical data, symptoms, and stress electrocardiographic data in identifying patients who will have a subsequent cardiac event.     

Multimodality treatment for retinoblastoma in children

A comprehensive programme was developed for the treatment of uni- and bilateral retinoblastoma in children with due regard to the disease stage by the TNM system. The use of the current sources of teletherapy and cyclic polychemotherapy expanded indications for organ-saving therapy at most common stages. Treatment by the program was performed in 202 patients, including 125 children with unilateral damage and 77 with bilateral damage. An attempt made treat 140 (75%) children at the first stage. More than 70% of cases were diagnosed as having disease stage T3 in one or two stage, while such patients underwent ocular enucleation. A complete or partial (more than 50%) tumor regression without signs of its progression for 2 years or more was achieved in 62% of cases. At the first stage of therapy, conservative therapy insignificantly affected the children's longevity in uncomplicated cases, which is particularly important in bilateral involvement, while this preserved the organ of vision in more than half the patients (62%). Five-year survival was 92 and 82% in unilateral retinoblastoma surgically treated and untreated, 83 and 84%, respectively. Adequate multimodality treatment brought about low incidence rates of recurrence and metastasis (10%) in conservative therapy and 7.7% among all patients.     

Biologic glue increases capillary ingrowth after cardiomyoplasty in an ischemic cardiomyopathy model

The authors investigated the multi-step mechanism of healing after cardiomyoplasty, focusing on the process of angiogenesis. The authors contend that enhancement of angiogenesis and prevention of ischemia-reperfusion injuries immediately after muscle mobilization will be effective in improving cardiomyoplasty results. After cardiomyoplasty, autologous biologic glue (ABG) was administered between the latissimus dorsi muscle (LDM) and myocardium. By 2 months, a new pseudo interlayer was present that bridged the gap between the LDM and myocardium. Neovascularization was visible in the form of numerous small capillaries. Marked degeneration of the LDM was noted, possibly caused by muscle ischemia-reperfusion damage after mobilization. Pockets were created of ischemic and nonischemic LDM to test for angiogenesis. One was left free of ABG (control); one received ABG only; one received ABG and pyrrolostatin. Some of the capillaries were large and had erythrocytes inside. biopsy samples showed 9.4 +/- 1.9% of the sample was occupied by blood vessels (compared with 3.6 +/- 0.7% in control muscle). These preliminary studies prove the feasibility of the authors' concept and provide evidence that angiogenesis can accelerate the healing process and provide an organic bridge between the LDM and myocardium after cardiomyoplasty.     

Childhood leukemia in Belarus before and after the Chernobyl accident

Childhood leukemia (ICD 204-208 [1]) incidence rates in the different regions of Belarus are reported for a period before and after the Chernobyl accident (1982-1994). There are, at this point, no recognizable trends towards higher rates.