Testing theoretical models of magnetic damping using an air track

Magnetic braking is a long-established application of Lenz's law. A rigorous analysis of the laws governing this problem involves solving Maxwell's equations in a time-dependent situation. Approximate models have been developed to describe different experiences related to this phenomenon. In this paper we present a new method for the analysis of the magnetic braking using a magnet fixed to the glider of an air track. The forces acting on the glider, a result of the eddy currents, can be easily observed and measured. As a consequence of the air track inclination, the glider accelerates at the beginning, although it asymptotically tends towards a uniform rectilinear movement characterized by a terminal speed. This speed depends on the interaction between the magnetic field and the conductivity properties of the air track. Compared with previous related approaches, in our experimental setup the magnet fixed to the glider produces a magnetic braking force which acts continuously, rather than over a short period of time. The experimental results satisfactorily concur with the theoretical models adapted to this configuration.Comment: 15 pages, 5 figure

Conversion Efficacy and Safety of Intravenous Ibutilide Compared With Intravenous Procainamide in Patients With Atrial Flutter or Fibrillation 11This study was sponsored by Pharmacia & Upjohn, Kalamazoo, Michigan.22See Appendix Afor a complete list of investigators and study sites.

AbstractObjectives. This multicenter study compared the efficacy and safety of ibutilide versus procainamide for conversion of recent-onset atrial flutter or fibrillation.Background. Ibutilide fumarate is an intravenous (IV) class III antiarrhythmic agent that has been shown to be significantly more effective than placebo in the pharmacologic conversion of atrial flutter and fibrillation to sinus rhythm. Procainamide is commonly used for conversion of recent-onset atrial fibrillation to normal sinus rhythm.Methods. One hundred twenty-seven patients (age range 22 to 92 years) with atrial flutter or fibrillation of 3 h to 90 days’ (mean 21 days) duration were randomized to receive either two 10-min IV infusions of 1 mg of ibutilide fumarate, separated by a 10-min infusion of 5% dextrose in sterile water, or three successive 10-min IV infusions of 400 mg of procainamide hydrochloride.Results. Of the 127 patients, 120 were evaluated for efficacy: 35 (58.3%) of 60 in the ibutilide group compared with 11 (18.3%) of 60 in the procainamide group had successful termination within 1.5 h of treatment (p < 0.0001). Seven patients were found to have violated the protocol and were not included in the final evaluation. In the patients with atrial flutter, ibutilide had a significantly higher success rate than procainamide (76% [13 of 17] vs. 14% [3 of 22], p = 0.001). Similarly, in the atrial fibrillation group, ibutilide had a significantly higher success rate than procainamide (51% [22 of 43] vs. 21% [8 of 38], p = 0.005). One patient who received ibutilide, which was found to be a protocol violation, had sustained polymorphic ventricular tachycardia requiring direct current cardioversion. Seven patients who received procainamide became hypotensive.Conclusions. This study establishes the superior efficacy of ibutilide over procainamide when administered to patients to convert either atrial fibrillation or atrial flutter to sinus rhythm. Hypotension was the major adverse effect seen with procainamide. A low incidence of serious proarrhythmia was seen with the administration of ibutilide occurring at the end of infusion

The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease

Proteasome Inhibitor Bortezomib Ameliorates Intestinal Injury in Mice

Background: Bortezomib is a proteasome inhibitor that has shown impressive efficacy in the treatment of multiple myeloma. In mice, the addition of dextran sulfate sodium (DSS) to drinking water leads to acute colitis that can serve as an experimental animal model for human ulcerative colitis. Methodology/Principal Findings: Bortezomib treatment was shown to potently inhibit murine DSS-induced colitis. The attenuation of DSS-induced colitis was associated with decreased inflammatory cell infiltration in the colon. Specifically, bortezomib-treated mice showed significantly decreased numbers of CD4 + and CD8 + T cells in the colon and mesenteric lymph nodes. Bortezomib treatment significantly diminished interferon (IFN)-c expression in the colon and mesenteric lymph nodes. Furthermore, cytoplasmic IFN-c production by CD4 + and CD8 + T cells in mesenteric lymph nodes was substantially decreased by bortezomib treatment. Notably, bortezomib enhanced T cell apoptosis by inhibiting nuclear factor-kB activation during DSS-induced colitis. Conclusions/Significance: Bortezomib treatment is likely to induce T cell death, thereby suppressing DSS-induced colitis by reducing IFN-c production

Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution

The cancer immunoediting hypothesis assumes the immune system sculpts the cancer genome. Here the authors show, in a mouse model, that neutral evolution outweighs the effects of immunoselection and that immune checkpoint blockade potentiates the immunoediting, switching the system to non-neutral evolution

‘Multi-Epitope-Targeted’ Immune-Specific Therapy for a Multiple Sclerosis-Like Disease via Engineered Multi-Epitope Protein Is Superior to Peptides

Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents. Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells). Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents. Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases

A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales