Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins

Microglial interaction with amyloid fibrils in the brains of Alzheimer's and prion disease patients results in the inflammatory activation of these cells. We observed that primary microglial cultures and the THP-1 monocytic cell line are stimulated by fibrillar beta-amyloid and prion peptides to activate identical tyrosine kinase-dependent inflammatory signal transduction cascades. The tyrosine kinases Lyn and Syk are activated by the fibrillar peptides and initiate a signaling cascade resulting in a transient release of intracellular calcium that results in the activation of classical PKC and the recently described calcium-sensitive tyrosine kinase PYK2. Activation of the MAP kinases ERK1 and ERK2 follows as a subsequent downstream signaling event. We demonstrate that PYK2 is positioned downstream of Lyn, Syk, and PKC. PKC is a necessary intermediate required for ERK activation. Importantly, the signaling response elicited by beta-amyloid and prion fibrils leads to the production of neurotoxic products. We have demonstrated in a tissue culture model that conditioned media from beta-amyloid- and prion-stimulated microglia or from THP-1 monocytes are neurotoxic to mouse cortical neurons. This toxicity can be ameliorated by treating THP-1 cells with specific enzyme inhibitors that target various components of the signal transduction pathway linked to the inflammatory responses.     

Oocysts of Cryptosporidium parvum and model sand surfaces in aqueous solutions: an atomic force microscope (AFM) study

Oocysts of C. parvum have been associated with several waterborne outbreaks of gastro-enteric disease. Currently, one of the main barriers to oocyst contamination of drinking waters is provided by sand-bed filtration. In this study an atomic force microscope (AFM) has been used to measure the force of interaction between oocysts of C. parvum and a model sand surface (silicate glass). The AFM force curves have been compared and contrasted with the corresponding electrical potentials obtained from electrophoretic measurements (zeta). It has been found that the surface of C. parvum oocysts possesses a hairy layer, most likely a result of surface proteins extending into solution. The hairy layer imposes a steric repulsion between the oocyst and sand surface, in addition to any electrostatic repulsion. The hairy layer collapsed to varying extents in the presence of dissolved calcium and dissolved organic carbon, indicating that the oocysts may be more readily adsorbed onto the model sand surface under these conditions. Conversely, as the two surfaces are pulled apart, the occasional attachment of oocyst surface proteins to the model sand surface can result in adhesion. The AFM results offer new insights into the oocyst surface of C. parvum, and the mechanism of interaction with model sand surfaces under conditions relevant to sand-bed filtration.     

Fault identification for robot manipulators

Several factors must be considered for robotic task execution in the presence of a fault, including: detection, identification, and accommodation for the fault. In this paper, a nonlinear observer is used to identify a class of actuator faults once the fault has been detected by some other method. Advantages of the proposed fault-identification method are that it is based on the nonlinear dynamic model of a robot manipulator (and hence, can be extended to a number of general Euler Lagrange systems), it does not require acceleration measurements, and it is independent from the controller. A Lyapunov-based analysis is provided to prove that the developed fault observer converges to the actual fault. Experimental results are provided to illustrate the performance of the identification method.     

Homography-based visual servo tracking control of a wheeled mobile robot

A visual servo tracking controller is developed in this paper for a monocular camera system mounted on an underactuated wheeled mobile robot (WMR) subject to nonholonomic motion constraints (i.e., the camera-in-hand problem). A prerecorded image sequence (e.g., a video) of three target points is used to define a desired trajectory for the WMR. By comparing the target points from a stationary reference image with the corresponding target points in the live image and the prerecorded sequence of images, projective geometric relationships are exploited to construct Euclidean homographies. The information obtained by decomposing the Euclidean homography is used to develop a kinematic controller. A Lyapunov-based analysis is used to develop an adaptive update law to actively compensate for the lack of depth information required for the translation error system. Experimental results are provided to demonstrate the control design.     

Analysis of grocery chain pharmacists' work-related behaviors

OBJECTIVE: To measure grocery chain pharmacists' work-related behaviors to assess the impact of a Pharmaceutical Care Certificate Program (PCCP) and other future interventions intended to alter pharmacists' practice behaviors. DESIGN: This study used multidimensional work sampling (MWS), a work measurement methodology that breaks "work" into three components: activity (what was done), contact (with whom the activity was performed), and function (the purpose or objective of the activity). Pharmacists were signaled at random intervals during the workday by a random signal generator. A selection was made from a list of items in each of the three dimensions of work to form an activity-contact-function combination code that described the work-related behavior at that point in time. SETTING AND PARTICIPANTS: Pharmacists in 15 grocery chain stores in the Indianapolis area; 20 pharmacists were enrolled in Purdue University's PCCP and 10 served as controls. Data were collected for a period of six weeks during April through June 1997 before the beginning of the PCCP program. MAIN OUTCOME MEASURES: Pharmacists' work-related behaviors. RESULTS: Writing/keyboarding was the most frequently recorded activity (22%), followed by one-to-one meetings (21.6%), and drug preparation (18%). Pharmacists spent most of their time working alone (62.9%), while a smaller but still substantial proportion of time was spent interacting with patients (17.9%). The most frequently recorded purpose (i.e., function) of pharmacists' activities was drug distribution (23.9%), followed by personal time (12.4%), receiving or transferring a medication order (10.2%), and patient counseling (6.6%). Out of a possible, 1,760 activity-contact-function combinations, 10 accounted for 46.3% of all reported observations, with "Prepare drug-Self-Drug distribution" representing the most frequently recorded activity-contact-function combination (15.7%). CONCLUSION: MWS is useful in helping grocery chain management better understand how pharmacy personnel are currently being utilized. This study provides a baseline for evaluating the impact of training programs or other alterations in the practice environment on pharmacists' work-related behaviors.     

Massage therapy effects

Massage therapy is older than recorded time, and rubbing was the primary form of medicine until the pharmaceutical revolution of the 1940s. Popularized again as part of the alternative medicine movement, massage therapy has recently received empirical support for facilitating growth, reducing pain, increasing alertness, diminishing depression, and enhancing immune function. In this article studies are reviewed that document these effects, and models are proposed for potential underlying mechanisms.     

Role rehearsal: a mock code program

A hospital implements a mock code program to increase nurses' comfort and skill with increased code arrest duties, improving their performance 95%.     

A randomized phase-II study of BB-10010 (macrophage inflammatory protein- 1alpha) in patients with advanced breast cancer receiving 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy

BB-10010 is a variant of the human form of macrophage inflammatory protein-1alpha (MIP-1alpha), which has been shown in mice to block the entry of hematopoietic stem cells into S-phase and to increase their self-renewal capacity during recovery from cytotoxic damage. Its use may constitute a novel approach for protecting the quality of the stem cell population and its capacity to regenerate after periods of cytotoxic treatment. Thirty patients with locally advanced or metastatic breast cancer were entered into the first randomized, parallel group controlled phase II study. This was designed to evaluate the potential myeloprotective effects of a 7-day regimen of BB-10010 administered to patients receiving six cycles of 5-fluorouracil (5-FU), adriamycin, and cyclophosphamide (FAC) chemotherapy. Patients were randomized, 10 receiving 100 microgram/kg BB-10010, 11 receiving 30 microgram/kg BB-10010, and nine control patients receiving no BB-10010. BB-10010 was well-tolerated in all patients with no severe adverse events related to the drug. Episodes of febrile neutropenia complicated only 4% of the treatment cycles and there was no difference in incidence between the treated and nontreated groups. Studies to assess the generation of progenitor cells in long-term bone marrow cultures were performed immediately preceding chemotherapy and at the end of six dosing cycles in 18 patients. Circulating neutrophils, platelets, CD 34(+) cells, and granulocyte/macrophage colony-forming cell (GM-CFC) levels were determined at serial time points in cycles 1, 3, and 6. The results showed similar hemoglobin and platelet kinetics in all three groups. On completion of the six treatment cycles, the average pretreatment neutrophil levels were reduced from 5.3 to 1.7 x 10(9)/L in the control patients and from 4.3 to 1.9 and 4.5 to 2.5 x 10(9)/L in the 30/100 microgram/kg BB-10010 groups, respectively. Relative to their pretreatment values, 50% of the patients receiving BB-10010 completed the treatment with neutrophil values significantly higher than any of the controls (P = .02). Mobilization of GM-CFC was enhanced by BB-10010 with an additional fivefold increase over that generated by chemotherapy alone, giving a maximal 25-fold increase over pretreatment values. Bone marrow progenitor assays before and after this standard regimen of chemotherapy indicated little long-term cumulative impairment to recovery from chemotherapy. Despite the limited cumulative damage to the bone marrow, which may have minimized the protective value of BB-10010 during this regimen of chemotherapy, better recovery of neutrophils in the later treatment cycles with BB-10010 was indicated in a number of patients.