Attenuated parasites

Whilst attenuated cercariae can induce protection reliably, their short lifespan (hours) makes them unsuitable for use in the field. Attempts were made to circumvent the problem by cryopreservation of attenuated larvae (Bickle and James, 1 978). Although up to 50% protection was achieved in cynomolgus monkeys (Murrell et a/., 1979), baboons (Damian et a/., 1984), mice (Lewis et a/., 1984) and guinea pigs (Xu et a/., 1 991), the lack of reproducibility in the cryopreservation process (Lewis et a/., 1984) meant that this approach eventually petered out. Even with improved cryopreservation, before such a vaccine could become a reality, the ethical and safety issues surrounding the administration to humans of large numbers of attenuated parasites with unknown migration characteristics would need to be addressed. 

Tarun, A. S., Dumpit, R. F., Camargo, N., Labaied, M., Liu, P., Takagi, A., Wang, R., and Kappe, S. H. (2007). Protracted sterile protection with Plasmodium yoelii pre-erythrocytic genetically attenuated parasite malaria vaccines is independent of significant liver-stage persistence and is mediated by CD8+ T cells. J. Infect. Dis. 196,608-616. 

For comparison purposes, two other MS systems have been used with in vitro grown parasite cultures. In the first case, a home-built miniaturized linear TOF multi-array analyzer1718 was interfaced to the frequency-tripled output at 355nm of a Q-switched Nd-YAG laser ( Polaris, New Wave Research, Fremont, CA). In this experiment the laser beam was not scanned, and the estimated laser fluence after attenuation was similar to that of the commer-... 

Several of the postulated roles for nematode-secreted AChEs assume that they gain access to the intestinal mucosa. Several possibilities exist for transport of parasite AChE across the epithelial cell barrier, such as (i) utilization of existing pathways for receptor-mediated transcytosis (ii) a paracellular route facilitated by parasite-secreted proteases as observed for a bacterial elastase (Azghani et al., 1993) and (iii) increased paracellular permeability resulting from inflammatory events in the mucosa. We consider the latter suggestion most likely, as this has been duplicated by ex vivo perfusion with rat mast cell protease II (Scudamore et al., 1995). Moreover, cholinergic stimulation attenuates epithelial barrier properties to macromolecules in rat ileal crypts (Phillips et al., 1987). 

Another interesting observation is that several species of filarial nematodes have been shown to express chitinase (Fuhrman, 1995). Indeed the chitinase of A. viteae infective stage larvae (L3) is the main target of the protective humoral immune response when jirds are vaccinated with irradiated attenuated L3s (Adam et al., 1996 see also Chapter 10). It remains to be established whether there is an interaction between the parasite s oligo-chitin A-glycans and chitinase and whether such an interaction has a role to play in parasite-host interaction. 

The overall ability of a power supply to attenuate disturbances at its input is expressed as its PSRR (power supply rejection ratio). In graphs, PSRR is usually plotted as a function of frequency. We will invariably find that the rejection ratio is very low at higher frequencies. One reason for this is that the Bode plot cannot really help because the open-loop gain is very small at these frequencies. The other reason is, even a tiny stray parasitic capacitance (e.g., across the power switch and inductor) presents such a low impedance to noise frequencies (whatever their origin) that almost all the noise present at the input migrates to the output unimpeded. In other words, the power stage attenuation (which we had earlier declared to be Vo/Rin) is also nonexistent for noise (and maybe even ripple) frequencies. The only noise attenuation comes from the LC filter (hopefully). 

Coulson, P.S., Smythies, L.E., Betts, C., Mabbott, N.A., Sternberg, J.M., Wei, X.G., Liew, F.Y. and Wilson, R.A. (1998) Nitric oxide produced in the lungs of mice immunized with the radiation-attenuated schistosome vaccine is not the major agent causing challenge parasite elimination. Immunology 93, 55-63. 

The purpose of this chapter is to review and discuss the preclinical safety evaluation strategy for vaccine approaches to the prophylaxis and treatment of viral diseases. This chapter will discuss the newer approaches to vaccination and will include recombinant proteins, peptides, polysaccharides, DNA plasmids, and viral vectors with and without adjuvants. It is outside the scope of this chapter to discuss whole cells expressing immunogens, live attenuated viruses, bacteria, or parasites. 

With the Chinese claims validated in 1984 by Klayman and coworkers,94 studies in the early 1980s rapidly addressed two key issues with the advancement of artemisinin as an antimalarial drug. One, how could it be made commercially and if so, what is its mode of action Although the former question was addressed,95,96 the lack in understanding its activity was reported by Gu.97 Here, evidence from prior studies indicated that, while active analogues could be prepared, including dihydroartemisinin and artemether (Figure 3.8), the endoperoxide function was key to this activity.98 In their work, Gu and co-workers postulated that the activity arose from modification of protein synthesis within the malaria parasite, Plasmodium falciparum 1 This was followed by a series of studies that indicated that the activity of artemisinin was attenuated by addition... 

Various bacterial vectors have been used to express a number of bacterial B. pertussis, S. pneumoniae, Y. pestis, and L. monocytogenes), viral (herpesvirus, influenza virus, human immunodeficiency virus, simian immunodeficiency virus, and hepatitis B virus), and parasitic (5. mansoni, and L. major) antigens. Significant improvements in attenuation of bacteria, and the stability, localization, and expression levels of heterologous antigens are required to market the bacterial vector-based vaccines for use in humans or animals. 

Chatfield, S.N. Roberts, M. Dougan, G. Hormaeche, C. Khan, C.M.A. The development of oral vaccines against parasitic diseases utilizing live attenuated salmonella. Parasitology 1995, IIO, S17-S24. 

Some investigators believe that the most important therapeutic application of IFNy will be to revert or maintain a Thl preferential response basically necessary for diverse successful defense reactions (e.g., against intracellular pathogens— namely parasites and virus—and tumor cells). IFNy has also been shown to be a suppressor of j3-amyloid precursor protein promoter activity and is the first cytokine reported to possess such down regulating effects. Attenuating [3-amyloid precursor protein gene expression may have relevance in diseases such as Alzheimer s disease, in which this protein has been implicated in neuropathological... 

The second problem highlighted by Equation (5) is the dependence of the sensitivity of the capacitive interface to parasitic capacitance, Cp2- This capacitance significantly degrades the sensor output as it approaches or exceeds the sense capacitance, Co- In principle, signal attenuation suffered as a result of excessive parasitics can be compensated by subsequent electronic amplification. In most cases, however, electronic noise and other errors are amplified also, negating any potential gain in sensor resolution. 

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