SummaryAccumulation of plasma cells in the synovium is one of the diagnostic hallmarks in the histopathological manifestations of rheumatoid arthritis (RA). This seems to be prominent even prior to significant B cell infiltration and/or formation of lymphoid follicles in the synovium. To clarify the mechanism of early plasma cell accumulation, we examined in situ expression of chemokines and their receptors using synovial targeting biopsy specimens, which were obtained under arthroscopy from early RA patients. By immunohistochemical staining, plasma cells were found to express a chemokine receptor CXCR3, while synovial fibroblasts in the synovial sublining regions expressed its ligand, Mig/CXCL9. By reverse transcription-polymerase chain reaction (RT-PCR), using targeted lesions of synovial tissues obtained by laser capture microdissection, expression levels of Mig/CXCL9 in the synovial sublining regions were remarkably high and were likely to be associated with interferon (IFN)-g g g g expression. Furthermore, cultured synovial fibroblasts were confirmed to produce Mig/CXCL9 upon stimulation with IFN-g g g g . Our results indicate that in the early stage of RA, plasma cells expressing CXCR3 may be recruited directly from the circulation into the synovial sublining regions by its ligand, Mig/CXCL9, produced by synovial fibroblasts.
A tetrapeptide (Gly-Gly-Tyr-Arg, GGYR), which is not transported by di- or tripeptide transporters, was glycosylated with p-(succinylamido)phenyl alpha- or beta-D-glucopyranoside (alpha,beta-SAPG) to investigate whether these glycosylated molecules are transported by the Na+-dependent D-glucose transporter. Their uptake into brush border membrane vesicles (BBMVs) and transport through the intestinal membrane were examined using the rapid filtration technique and the everted sac method. It was observed that glycosylation at the alpha-amino position of GGYR increased resistance to aminopeptidase activity and inhibited its degradation. When alpha- and beta-SAPG-GGYR were incubated with BBMVs, overshoot uptake was observed about 2 min after the start of incubation in the presence of an inward Na+ gradient. This uptake remained unaffected by the addition of GGYR while it was significantly inhibited when Na+ was replaced with K+ or alpha- and beta-SAPG-GGYR were incubated with BBMVs at 4 degrees C. Uptake was also markedly inhibited either with 1 mM phloridzin or 10 mM D-glucose. These findings suggested that the Na+-dependent glucose transporter (SGLT-1) played an important role in the uptake of both alpha- and beta-SAPG-GGYR into BBMVs. A comparison of alpha- with beta-SAPG-GGYR revealed that the amount of beta-SAPG-GGYR taken up was greater than that of alpha-SAPG-GGYR. From the everted sac method data, it was shown that the elimination clearance from the mucosal side, CLel, and permeation clearance to the serosal side, CLp, were 15.82+/-6.83 and 0.83+/-0.06 microL/min/cm for alpha-SAPG-GGYR and 44.52+/-3.61 and 3.50+/-0.81 microL/min/cm for beta-SAPG-GGYR, respectively, and that alpha-SAPG-GGYR was more resistant to enzymatic degradation than beta-SAPG-GGYR. Permeation of both alpha- and beta-SAPG-GGYR was inhibited in the presence of D-glucose and in the absence of a Na+ gradient, suggesting that both alpha- and beta-SAPG-GGYR were transported by the Na+-dependent D-glucose transporter. The permeation clearance transported by the Na+-dependent D-glucose transporter, (CLp)Na+, of beta-SAPG-GGYR was about 5 times greater than that for alpha-SAPG-GGYR. This result may be ascribable to the fact that the beta-form of glucose has higher affinity to SGLT-1 than the alpha-form. The results of the present study encourage further investigations on improvements in intestinal absorption of peptide drugs by glycosylation.
PURPOSE. We created implantable intraocular devices capable of constant and continuous rapamycin release on the scale of months to years.METHODS. Polycaprolactone (PCL) thin films were used to encapsulate rapamycin to create implantable and biodegradable intraocular devices. Different film devices were studied by modifying the size, thickness, and porosity of the PCL films.RESULTS. In vitro release of rapamycin was observed to be constant (zero-order) through 14 weeks of study. Release rates were tunable by altering PCL film porosity and thickness. In vivo release of rapamycin was observed out through 16 weeks with concentrations in the retinachoroid in the therapeutic range. Rapamycin concentration in the blood was below the lower limit of quantification. The drug remaining in the device was chemically stable in vitro and in vivo, and was sufficient to last for upwards of 2 years of total release. The mechanism of release is related to the dissolution kinetics of crystalline rapamycin.CONCLUSIONS. Microporous PCL thin film devices demonstrate good ocular compatibility and the ability to release rapamycin locally to the eye over the course of many weeks.
Among Japanese children, food allergy and parents' history of allergy are risk factors for WP, ES or RS. However, early day-care attendance and presence of older siblings might be protective factors against RS. Infections in early life may affect the prevalence of rhinoconjunctivitis in six-year-old children.
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