Lithium peroxide test program Final report

Experimental design and performance data on carbon dioxide and oxygen control for portable life support system using lithium peroxid

Molecular Mechanisms Involved in Vascular Interactions of the Lyme Disease Pathogen in a Living Host

Hematogenous dissemination is important for infection by many bacterial pathogens, but is poorly understood because of the inability to directly observe this process in living hosts at the single cell level. All disseminating pathogens must tether to the host endothelium despite significant shear forces caused by blood flow. However, the molecules that mediate tethering interactions have not been identified for any bacterial pathogen except E. coli, which tethers to host cells via a specialized pillus structure that is not found in many pathogens. Furthermore, the mechanisms underlying tethering have never been examined in living hosts. We recently engineered a fluorescent strain of Borrelia burgdorferi, the Lyme disease pathogen, and visualized its dissemination from the microvasculature of living mice using intravital microscopy. We found that dissemination was a multistage process that included tethering, dragging, stationary adhesion and extravasation. In the study described here, we used quantitative real-time intravital microscopy to investigate the mechanistic features of the vascular interaction stage of B. burgdorferi dissemination. We found that tethering and dragging interactions were mechanistically distinct from stationary adhesion, and constituted the rate-limiting initiation step of microvascular interactions. Surprisingly, initiation was mediated by host Fn and GAGs, and the Fn- and GAG-interacting B. burgdorferi protein BBK32. Initiation was also strongly inhibited by the low molecular weight clinical heparin dalteparin. These findings indicate that the initiation of spirochete microvascular interactions is dependent on host ligands known to interact in vitro with numerous other bacterial pathogens. This conclusion raises the intriguing possibility that fibronectin and GAG interactions might be a general feature of hematogenous dissemination by other pathogens

Sterilization of men with intellectual disabilities: whose best interest is it anyway?

This article examines the ethical and legal issues raised by the involuntary sterilization of men with intellectual disability. It traces how, after the demise of eugenic reasoning, social policies of normalization and care in the community provided new justifications for sterilizations. It also examines how, ironically, modern arguments about promoting male sexual freedom have come to be used as a justification to sterilize. Through examination of recent cases on the sterilization of men with intellectual disabilities, this article explores the legal framework of the ‘best interests’ test and the ‘least restrictive alternative’ provisions in the Mental Capacity Act 2005 and argues that sterilization is usually unnecessary, disproportionate and not the least restrictive option. It also argues that the least restrictive alternative provisions contained in the 2005 Act need to be more rigorously applied

Monocoque structure for the SKITTER three-legged walker

The SKITTER 2 design is a monocoque version of the proposed lunar three-legged walker. By the definition of monocoque, the body and legs are a shell with no internal ribbing or supports added for absorbing stresses. The purpose of the monocoque is to encase the elements used for power transmission, power supply, and control of the motion. The material for the structure is a vinyl ester resin, Derakane 8084. This material is easily formable and locally obtainable. The body consists of a hexagonally shaped cylinder with truncated hexagonal pyramids on the top and botton. The legs are eight inch diameter cylinders. The legs are comprised of a tibia section and a femur section. The SKITTER 2 is powered by six actuators which provide linear forces that are transformed into rotary torques by a series of chains and sprockets. The joints connect the femur to the body and the tibia to the femur. Surrounding the joints are flexible rubber hoses that fully encase the chains and sprockets. The SKITTER 2 is capable of walking upside down, righting itself after being overturned, and has the ability to perform in many environments. Applications for this walker include lunar transport or drilling, undersea exploration, and operation in severe surroundings such as arctic temperatures or high radiation

Fulvestrant: pharmacokinetics and pharmacology

Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist activity and a novel pharmacological profile. Fulvestrant has been shown to significantly reduce cellular levels of the ER and progesterone receptor in both preclinical studies and in clinical trials of postmenopausal women with primary breast cancer. This paper reviews the pharmacokinetics and metabolism of fulvestrant, which support the rationale for drug delivery as a single, once-monthly intramuscular injection, and show that this agent has minimal potential to be the subject, or cause, of significant cytochrome p450-mediated drug interactions

The Role of I Region Gene Products in Macrophage - T Lymphocyte Interaction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73965/1/j.1600-065X.1978.tb00400.x.pd

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

Oncogenomic studies indicate that copy number variation (CNV) alters genes involved in tumor progression; however, identification of specific driver genes affected by CNV has been difficult, as these rearrangements are often contained in large chromosomal intervals among several bystander genes. Here, we addressed this problem and identified a CNV-targeted oncogene by performing comparative oncogenomics of human and zebrafish melanomas. We determined that the gene encoding growth differentiation factor 6 (GDF6), which is the ligand for the BMP family, is recurrently amplified and transcriptionally upregulated in melanoma. GDF6-induced BMP signaling maintained a trunk neural crest gene signature in melanomas. Additionally, GDF6 repressed the melanocyte differentiation gene MITF and the proapoptotic factor SOX9, thereby preventing differentiation, inhibiting cell death, and promoting tumor growth. GDF6 was specifically expressed in melanomas but not melanocytes. Moreover, GDF6 expression levels in melanomas were inversely correlated with patient survival. Our study has identified a fundamental role for GDF6 and BMP signaling in governing an embryonic cell gene signature to promote melanoma progression, thus providing potential opportunities for targeted therapy to treat GDF6-positive cancers

Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs