SUMMARYPolyarthritis may result from the haematogenous distribution of arthritogenic effector lymphocytes that emerge in the efferent lymph and pass through the thoracic duct (TD) to the circulation. We therefore examined whether TD cells collected from rats in the late prodrome of adjuvant-induced arthritis (AA) could transfer polyarthritis adoptively and whether these cells included a subpopulation of arthritogenic cells that could be identified phenotypically. Unfractionated TD cells collected from donor rats 9 days after adjuvant inoculation were injected intravenously into normal syngeneic recipients in numbers equivalent to the overnight harvest from a single donor. TD cell subpopulations, equivalent in number to proportions in the same inoculum, were prepared by negative selection. Unfractionated TD cells transferred polyarthritis without in vitro stimulation or conditioning of recipient animals. Abrogation of arthritogenicity by depletion of a/b TCR 1 cells showed that the polyarthritis was transferred by T cells. Negatively selected CD4 1 but not CD8 1 TD cells transferred AA. An arthritogenic subpopulation of CD4 1 T cells, enriched by either negative or positive selection, expressed the activation markers CD25 (IL-2 receptor alpha), CD71 (transferrin receptor), CD134 (OX40 antigen) and MHC class II. Cells expressing these markers were more numerous in TD lymph from arthritic rats than in lymph from normal rats and they included the majority of large CD4 1 T cells. Thus, arthritogenic effector T cells bearing activation markers are released into the central efferent lymph in the late prodrome of AA. Recruitment of these arthritogenic cells to synovium probably determines the polyarticular pattern of AA.
Fetuses swallow large volumes of amniotic fluid. Absence of swallowing results in gastrointestinal tract (GIT) growth deficits. While it is not yet known to what extent the growth factors present in amniotic fluid are involved in GIT ontogeny, milk-derived growth factors are considered to be important for neonatal growth. Our experiment tested the hypothesis that a luminal growth factor (insulin-like growth factor-I, IGF-I) can sustain or promote GIT growth in utero in a model of gastrointestinal tract growth retardation. Ten-day infusion of either human recombinant IGF-I or vehicle into twin fetal sheep at 80 days gestation via an indwelling esophageal catheter resulted in altered GIT growth. Weight of the forestomach and small intestine increased. Significant histological changes were noted in the proximal small intestine, i.e. the region most exposed to the luminal infusion. Mucosal tissues were reduced in size. While the enterocytes in the proximal small intestine were generally more mature with regard to the ontogeny of the apical endocytic complex (which is responsible for uptake and transport of whole peptides), there were also many abnormal cytological features present. These included the development of large lysosomal-like inclusion bodies and many surfactant-like particles within the apical cytoplasm. Plasma IGF-I levels were on average 20% higher in treated siblings, suggesting that luminal IGF-I crossed the fetal gut and entered blood. IGF-II levels were not significantly affected. These observations are consistent with the suggestion that growth factors, which are present in swallowed amniotic fluid, influence fetal ontogeny.
Microbubbles stabilized by an outer lipid shell have been studied extensively for both diagnostic and therapeutic applications. The shell composition can significantly influence microbubble behavior, but performing quantitative measurements of shell properties is challenging. The aim of this study is to investigate the use of spectral imaging to characterize the surface properties of a range of microbubble formulations representing both commercial and research agents. A lipophilic dye, C-laurdan, whose fluorescence emission varies according to the properties of the local environment, was used to compare the degree and uniformity of the lipid order in the microbubble shell, and these measurements were compared with the acoustic response and stability of the different formulations. Spectral imaging was found to be suitable for performing rapid and hence relatively high throughput measurements of microbubble surface properties. Interestingly, despite significant differences in lipid molecule size and charge, all of the different formulations exhibited highly ordered lipid shells. Measurements of liposomes with the same composition and the debris generated by destroying lipid microbubbles with ultrasound (US) showed that these exhibited a lower and more varied lipid order than intact microbubbles. This suggests that the high lipid order of microbubbles is due primarily to compression of the shell as a result of surface tension and is only minimally affected by composition. This also explains the similarity in acoustic response observed between the formulations, because microbubble dynamics are determined by the diameter and shell viscoelastic properties that are themselves a function of the lipid order. Within each population, there was considerable variability in the lipid order and response between individual microbubbles, suggesting the need for improved manufacturing techniques. In addition, the difference in the lipid order between the shell and lipid debris may be important for therapeutic applications in which shedding of the shell material is exploited, for example, drug delivery.
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