The shapes of the motor domains of two oppositely directed microtubule motors, ncd and kinesin: a neutron scattering study

The shapes of the motor domains of kinesin and ncd, which move in opposite directions along microtubules, have been investigated. Using proteins expressed in Escherichia coli, it was found that at high salt (> 200 mM) Drosophila ncd motor domain (R335-K700) and human kinesin motor domain (M1-E349) were both sufficiently monomeric to allow an accurate determination of their radii of gyration (Rg) and their molecular weights. The measured Rg values of the ncd and kinesin motor domains in D2O were 2.06 +/- 0.06 and 2.05 +/- 0.04 nm, respectively, and the molecular weights were consistent with those computed from the amino acid compositions. Fitting of the scattering curves to approximately 3.5 nm resolution showed that the ncd and kinesin motor domains can be described adequately by triaxial ellipsoids having half-axes of 1.42 +/- 0.38, 2.24 +/- 0.44, and 3.65 +/- 0.22 nm, and half-axes of 1.52 +/- 0.23, 2.00 +/- 0.25, and 3.73 +/- 0.10 nm, respectively. Both motor domains are described adequately as somewhat flattened prolate ellipsoids with a maximum dimension of approximately 7.5 nm. Thus, it appears that the overall shapes of these motor domains are not the major determinants of the directionality of their movement along microtubules.     

Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study

BACKGROUND: Dual therapy with ticlopidine and aspirin has been shown to be as effective as or more effective than conventional anticoagulation in patients with an optimal result after implantation of intracoronary metallic stents. However, the safety and efficacy of antiplatelet therapy alone in an unselected population has not been evaluated. METHODS: Patients were randomized to conventional anticoagulation or to treatment with antiplatelet therapy alone. Indications for stenting were classified as elective (decided before the procedure) or unplanned (to salvage failed angioplasty or to optimize the results of balloon angioplasty). After stenting, patients received aspirin and either ticlopidine or conventional anticoagulation (heparin or oral anticoagulant). The primary end point was the occurrence of bleeding or peripheral vascular complications; secondary end points were cardiac events (death, infarction, or stent occlusion) and duration of hospitalization. RESULTS: In 13 centers, 236 patients were randomized to anticoagulation and 249 to antiplatelet therapy. Stenting was elective in 58% of patients and unplanned in 42%. Stent implantation was successfully achieved in 99% of patients. A primary end point occurred in 33 patients (13.5%) in the antiplatelet group and 48 patients (21%) in the anticoagulation group (odds ratio=0.6 [95% CI 0.36 to 0.98], P=0.03). Major cardiac-related events in electively stented patients were less common (odds ratio=0.23 [95% CI 0.05 to 0.91], P=0.01) in the antiplatelet group (3 of 123, 2.4%) than the anticoagulation group (11 of 111, 9.9%). Hospital stay was significantly shorter in the antiplatelet group (4.3+/-3.6 versus 6. 4+/-3.7 days, P=0.0001). CONCLUSIONS: Antiplatelet therapy after coronary stenting significantly reduced rates of bleeding and subacute stent occlusion compared with conventional anticoagulation.     

In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission

PURPOSE: To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS: Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS: Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION: This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.     

Animal models of ALS

Animal models of amyotrophic lateral sclerosis (ALS) provide a unique opportunity to study this incurable and fatal human disease both clinically and pathologically. This is particularly true for certain pathological and therapeutic studies that are impractical or impossible to perform in human patients. Nonetheless, postmortem ALS tissue remains the "gold standard" against which pathologic findings in animal models must be compared. Four natural disease models have been most extensively studied, including three mouse models: motor neuron degeneration (Mnd), progressive motor neuronopathy (pmn), wobbler, and one canine model: hereditary canine spinal muscular atrophy (HCSMA). The wobbler mouse has been the most extensively studied of these models with analyses of clinical, pathological (perikaryon, axon, muscle), and biochemical features. Experimentally induced ALS animal models have allowed controlled testing of various neurotoxic, viral and immune-mediated mechanisms. Molecular techniques have recently generated mouse models in which genes relevant to the human disease or motor neuron biology have been manipulated. The most clinically relevant of these is a transgenic mouse overexpressing the mutated SOD1 gene of FALS patients, which has already provided significant insights into mechanisms of motor neuron degeneration in this disease. Because no single animal model perfectly reflects all the clinical and pathological characteristics of ALS, study of selected features from the most relevant models will contribute to a better understanding of the pathogenesis and/or etiology of this disease.     

Body thiamine level in acute alcohol psychoses

PURPOSE: To compare admission data and academic performances of medical students younger and older than 25, and to qualify older students' experiences and perceptions in medical school. METHOD: The authors reviewed 1988-1991 data for applications to the McGill University Faculty of Medicine. Data included GPAs and MCAT scores, as well as ratings for reference letters, autobiographical statements, and interviews. For those same years, the authors measured students' academic performances in the preclinical and clinical years. The authors compared the data by students' age: "younger" students, aged 17 to 24; and "older" students, aged 25 and above. All enrolled students took the Derogatis Stress Profile, and the older students participated in focus groups. RESULTS: The older applicants had lower GPAs and MCAT scores, but higher interview and reference letter ratings. For older accepted students, basic science course scores were lower than those of younger students, but clinical scores did not differ significantly between the groups. The two groups had similar stress levels, although older students tested lower in driven behavior, relaxation potential, attitude posture, and hostility. In focus groups, the older students spoke of learning style differences, loss of social support, and loss of professional identity. CONCLUSION: Different scores in admission criteria suggest that McGill uses different standards to select older medical students. Older students admitted under different criteria, however, do just as well as do younger students by their clinical years. A broad-based study of admission criteria and outcomes for the older student population is warranted.     

Migration and right atrial perforation of an Accufix atrial lead retention wire following partial lead removal during myomectomy

A 36-year-old man with a history of hypertrophic obstructive cardiomyopathy presented to the emergency room with "stabbing" chest pain. He had undergone dual-chamber pacemaker implantation in 1993 using an atrial lead (Accufix; Telectronics; Englewood, Colo) and a myomectomy in 1996 during which the distal portion of the atrial lead was removed. Digital fluoroscopy revealed that the retention wire had migrated out of the remaining atrial lead and perforated the right atrium. The retention wire was successfully removed percutaneously. The need for complete removal of the retention wire in the Accufix lead at the time of open-heart surgery is emphasized.     

Detection of foodborne pathogens using DNA probes and a dipstick format

The detection of foodborne microorganisms has traditionally been done using microbiologically based methods. Such "gold standard" methods are generally reliable but have the disadvantages of being labor intensive, subjective, and time consuming. Over the last several years, the development of DNA probe-based methods has simplified the methods used to detect organisms such as Salmonella, Listeria, and E. coli by targeting the unique DNA or RNA sequences of these organisms using DNA probes and nonradioactive detection.     

Activation of the mouse heart adenosine 5',5"'-P1-P4-tetraphosphate receptor

We have previously demonstrated that mouse brain membrane fractions have a specific, saturable receptor for diadenylated nucleotides. Binding is specific for two adenosines, and the length of the phosphate bridge is critical, with four phosphates being optimal [Hilderman et al. (1991) J. Biol. Chem. 266, 6915-6918]. In this report, we demonstrate that adenosine 5',5"'-P1,P4-tetraphosphate (Ap4A) binding to its receptor is dependent upon an activation step that requires divalent cations and a serine protease. Monoclonal antibodies (Mabs) are identified that inhibit Ap4A binding to its membrane receptor. These antibodies recognize a 212-kDa membrane protein. However, SDS-PAGE analysis of Ap4A cross-linked to membrane fractions reveals that Ap4A is not attached to the 212-kDa peptide but to a 30-kDa polypeptide. Appearance of the 30-kDa polypeptide is dependent on the activation step, and one of the inhibitory antibodies blocks its appearance. We suggest that the protease-dependent processing step involves cleavage of the 212-kDa component with the appearance of an active 30-kDa receptor.