IFN-α/β Induction by dsRNA and Toll-Like Receptors Shortens Allograft Survival Induced by Costimulation Blockade: A Dissertation

Costimulation blockade protocols are promising alternatives to the use of chronic immunosuppression for promoting long-term allograft survival. However, the efficacy of costimulation blockade-based protocols is decreased by environmental insults such as viral infections. For example, lymphocytic choriomeningitis virus (LCMV) infection at the time of costimulation blockade treatment abrogates skin allograft survival in mice. In this dissertation, we test the hypothesis that viruses shorten allograft survival by activating the innate immune system through pattern-recognition receptors (PRRs), such as toll-like receptors (TLRs). To investigate the role of innate immunity in shortening allograft survival, costimulation blockade-treated mice were co-injected with TLR2 (Pam3Cys), TLR3 (polyinosinic:polycytidylic acid, poly(I:C)), TLR4 (lipopolysaccharide, LPS), or TLR9 (CpG DNA) agonists, followed by transplantation with skin allografts 7 days later. Costimulation blockade prolonged skin allograft survival that was shortened in mice coinjected with TLR agonists. To investigate the underlying mechanisms of this observation, we used synchimeric mice, which circulate trace populations of anti-H2b transgenic alloreactive CD8+ T cells. In synchimeric mice treated with costimulation blockade, co-administration of all four TLR agonists prevented deletion of alloreactive CD8+ T cells. These alloreactive CD8+ T cells 1) expressed the proliferation marker Ki-67, 2) upregulated CD44, and 3) failed to undergo apoptosis. We also demonstrate that costimulation blockade-treated CD8α-deficient mice exhibit prolonged allograft survival when co-injected with LPS. These data suggest that TLR agonists shorten allograft survival by impairing the apoptosis of alloreactive CD8+T cells. We further delineate the mechanism by which TLR agonists shorten allograft survival by demonstrating that LPS and poly(I:C) fail to shorten allograft survival in IFNRI- deficient mice. Interestingly, the ability of poly(I:C) to more potently induce IFN-α/β than LPS correlates with its superior abilities to shorten islet allograft survival and induce allo-specific CTL activity as measured by an in vivo cytotoxicity assay. The ability to shorten allograft survival and induce IFN-α/β is a TLR-dependent process for LPS, but is a TLR-independent process for poly(I:C). Strikingly, the injection of IFN-β impairs alloreactive CD8+T cell deletion and shortens allograft survival, similar to LPS and poly(I:C). These data suggest that LPS and poly(I:C) shorten allograft survival by inducing IFN-α/β through two different mechanisms. Finally, we present data showing that viruses (LCMV, Pichinde virus, murine cytomegalovirus and vaccinia virus) impair alloreactive CD8+T cell deletion and shorten allograft survival, in a manner comparable to LPS and poly(I:C). Similar to LPS, LCMV and MCMV exhibit an impaired ability to shorten allograft survival in MyD88-deficient mice. These data suggest that the MyD88 pathway is required for certain viruses and TLR-agonists to shorten allograft survival. In this dissertation, we present data supporting an important role for TLRs and IFN- α/β in shortening allograft induced by costimulation blockade. Our findings suggest that targeting these pathways during the peri-transplant period may enhance the efficacy of costimulation blockade protocols in the clinic

The Macrame 1024 node switching network

The work reported involves the construction of a large modular testbed using IEEE 1355 DS link technology. A thousand nodes will be interconnected by a switching fabric based on the STC104 packet switch. The system has been designed and constructed in a modular way in order to allow a variety of different network topologies to be investigated. Network throughput and latency have been studied for different network topologies under various traffic conditions

Investigation of the Repassivation Process of CoCrMo in Simulated Biological Fluids

A thorough investigation into the repassivation process of CoCrMo in multiple simulated biological environments has been undertaken, looking in detail at both the kinetics and composition of the reformed oxide film. Specific focus of this research was aimed at determining the effect of bovine serum albumin (BSA) on these features. The kinetics of repassivation were obtained by using a variety of electrochemical techniques. The current transients formed were fitted to a second-order decay curve, which accouts for two separate phases: coverage and growth. The reformation of the passive film was fastest in a phosphate buffered saline environment, with the presence of BSA delaying this process because it inhibits the oxygen-reduction reaction as it obstructs the active sites of the alloy when adsorbed onto the surface. The composition of the newly formed film was analyzed with x-ray photoelectron spectroscopy. As expected, the film was primarily composed of chromium (III) oxide with small contributions from cobalt and molybdenum oxides. In the presence of BSA, the quantity of molybdenum within the film was drastically reduced; it was shown to be extracted into the bulk solution via inductively coupled mass spectroscopy. This is observed because BSA is able to complex preferentially to the molybdenum ions when the alloy is exposed, extracting them into solution and altering the composition and integrity of the film

Uncovering Spiral Structure in Flocculent Galaxies

We present K'(2.1 micron) observations of four nearby flocculent spirals, which clearly show low-level spiral structure and suggest that kiloparsec-scale spiral structure is more prevalent in flocculent spirals than previously supposed. In particular, the prototypical flocculent spiral NGC 5055 is shown to have regular, two-arm spiral structure to a radius of 4 kpc in the near infrared, with an arm-interarm contrast of 1.3. The spiral structure in all four galaxies is weaker than that in grand design galaxies. Taken in unbarred galaxies with no large, nearby companions, these data are consistent with the modal theory of spiral density waves, which maintains that density waves are intrinsic to the disk. As an alternative, mechanisms for driving spiral structure with non-axisymmetric perturbers are also discussed. These observations highlight the importance of near infrared imaging for exploring the range of physical environments in which large-scale dynamical processes, such as density waves, are important.Comment: 12 pages AASTeX; 3 compressed PS figures can be retrieved from ftp://ftp.astro.umd.edu/pub/michele as file thornley.tar (1.6Mbytes). Accepted to Ap.J. Letters.(Figures now also available here, and from ftp://ftp.astro.umd.edu/pub/michele , in GIF format.

Viral Infection: A Potent Barrier to Transplantation Tolerance

Transplantation of allogeneic organs has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression that is required for organ allograft survival increases the risk for infection and neoplasia and has direct organ toxicity. The establishment of transplantation tolerance, which obviates the need for chronic immunosuppression, is the ultimate goal in the field of transplantation. Many experimental approaches have been developed in animal models that permit long-term allograft survival in the absence of chronic immunosuppression. These approaches function by inducing peripheral or central tolerance to the allograft. Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade. However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection. In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality. In this review, we discuss how viruses modulate the induction and maintenance of transplantation tolerance

Gross Domestic Product (GDP) and productivity of schizophrenia trials: an ecological study

The 5000 randomised controlled trials (RCTs) in the Cochrane Schizophrenia Group's database affords an opportunity to research for variables related to the differences between nations of their output of schizophrenia trials. Ecological study – investigating the relationship between four economic/demographic variables and number of schizophrenia RCTs per country. The variable with closest correlation was used to predict the expected number of studies. GDP closely correlated with schizophrenia trial output, with 76% of the total variation about the Y explained by the regression line (r = 0.87, 95% CI 0.79 to 0.92, r2 = 0.76). Many countries have a strong tradition of schizophrenia trials, exceeding their predicted output. All nations with no identified trial output had GDPs that predicted zero trial activity. Several nations with relatively small GDPs are, nevertheless, highly productive of trials. Some wealthy countries seem either not to have produced the expected number of randomised trials or not to have disseminated them to the English-speaking world. This hypothesis-generating study could not investigate causal relationships, but suggests, that for those seeking all relevant studies, expending effort searching the scientific literature of Germany, Italy, France, Brazil and Japan may be a good investment

Symbiosis between the TRECVid benchmark and video libraries at the Netherlands Institute for Sound and Vision

Audiovisual archives are investing in large-scale digitisation efforts of their analogue holdings and, in parallel, ingesting an ever-increasing amount of born- digital files in their digital storage facilities. Digitisation opens up new access paradigms and boosted re-use of audiovisual content. Query-log analyses show the shortcomings of manual annotation, therefore archives are complementing these annotations by developing novel search engines that automatically extract information from both audio and the visual tracks. Over the past few years, the TRECVid benchmark has developed a novel relationship with the Netherlands Institute of Sound and Vision (NISV) which goes beyond the NISV just providing data and use cases to TRECVid. Prototype and demonstrator systems developed as part of TRECVid are set to become a key driver in improving the quality of search engines at the NISV and will ultimately help other audiovisual archives to offer more efficient and more fine-grained access to their collections. This paper reports the experiences of NISV in leveraging the activities of the TRECVid benchmark

The inter-rater reliability of the diagnosis of surgical site infection in the context of a clinical trial.

ObjectivesThe diagnosis of surgical site infection following endoprosthetic reconstruction for bone tumours is frequently a subjective diagnosis. Large clinical trials use blinded Central Adjudication Committees (CACs) to minimise the variability and bias associated with assessing a clinical outcome. The aim of this study was to determine the level of inter-rater and intra-rater agreement in the diagnosis of surgical site infection in the context of a clinical trial.Materials and methodsThe Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY) trial CAC adjudicated 29 non-PARITY cases of lower extremity endoprosthetic reconstruction. The CAC members classified each case according to the Centers for Disease Control (CDC) criteria for surgical site infection (superficial, deep, or organ space). Combinatorial analysis was used to calculate the smallest CAC panel size required to maximise agreement. A final meeting was held to establish a consensus.ResultsFull or near consensus was reached in 20 of the 29 cases. The Fleiss kappa value was calculated as 0.44 (95% confidence interval (CI) 0.35 to 0.53), or moderate agreement. The greatest statistical agreement was observed in the outcome of no infection, 0.61 (95% CI 0.49 to 0.72, substantial agreement). Panelists reached a full consensus in 12 of 29 cases and near consensus in five of 29 cases when CDC criteria were used (superficial, deep or organ space). A stable maximum Fleiss kappa of 0.46 (95% CI 0.50 to 0.35) at CAC sizes greater than three members was obtained.ConclusionsThere is substantial agreement among the members of the PARITY CAC regarding the presence or absence of surgical site infection. Agreement on the level of infection, however, is more challenging. Additional clinical information routinely collected by the prospective PARITY trial may improve the discriminatory capacity of the CAC in the parent study for the diagnosis of infection.Cite this article: J. Nuttall, N. Evaniew, P. Thornley, A. Griffin, B. Deheshi, T. O'Shea, J. Wunder, P. Ferguson, R. L. Randall, R. Turcotte, P. Schneider, P. McKay, M. Bhandari, M. Ghert. The inter-rater reliability of the diagnosis of surgical site infection in the context of a clinical trial. Bone Joint Res 2016;5:347-352. DOI: 10.1302/2046-3758.58.BJR-2016-0036.R1

Measuring subdiffusion parameters

We propose a method to extract from experimental data the subdiffusion parameter $\alpha$ and subdiffusion coefficient $D_\alpha$ which are defined by means of the relation $=2D_\alpha/\Gamma(1+\alpha) t^\alpha$ where $$ denotes a mean square displacement of a random walker starting from $x=0$ at the initial time $t=0$. The method exploits a membrane system where a substance of interest is transported in a solvent from one vessel to another across a thin membrane which plays here only an auxiliary role. Using such a system, we experimentally study a diffusion of glucose and sucrose in a gel solvent. We find a fully analytic solution of the fractional subdiffusion equation with the initial and boundary conditions representing the system under study. Confronting the experimental data with the derived formulas, we show a subdiffusive character of the sugar transport in gel solvent. We precisely determine the parameter $\alpha$, which is smaller than 1, and the subdiffusion coefficient $D_\alpha$.Comment: 17 pages, 9 figures, revised, to appear in Phys. Rev.