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Objective. Rheumatoid arthritis (RA) is classically thought of as a Th1, T lymphocyte-driven disease of the adaptive immune system. However, cells of the innate immune system, including neutrophils, are prevalent within the diseased joint, and accumulate in large numbers. This study was undertaken to determine whether cells of the rheumatoid stromal microenvironment could establish an inflammatory environment in which endothelial cells are conditioned in a diseasespecific manner to support neutrophil recruitment.Methods. Human umbilical vein endothelial cells (ECs) and fibroblasts isolated from the synovium or skin of RA patients were established in coculture on opposite sides of porous transwell filters. After 24 hours of EC conditioning, the membranes were incorporated into a parallel-plate, flow-based adhesion assay and levels of neutrophil adhesion to ECs were measured.Results. ECs cocultured with synovial, but not skin, fibroblasts could recruit neutrophils in a manner that was dependent on the number of fibroblasts. Antibody blockade of P-selectin or E-selectin reduced neutrophil adhesion, and an antibody against CD18 (the ␤2 integrin) abolished adhesion. Blockade of CXCR2, but not CXCR1, also greatly inhibited neutrophil recruitment. Interleukin-6 (IL-6) was detectable in coculture supernatants, and both IL-6 and neutrophil adhesion were reduced in a dose-dependent manner by hydrocortisone added to cocultures. Antibody blockade of IL-6 also effectively abolished neutrophil adhesion.Conclusion. Synovial fibroblasts from the rheumatoid joint play an important role in regulating the recruitment of inflammatory leukocytes during active disease. This process may depend on a previously unsuspected route of IL-6-mediated crosstalk between fibroblasts and endothelial cells.

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The preparation of ABA type block copoly(ester-b-carbonate-bester) from a mixture of ε-caprolactone, cyclohexene oxide, and carbon dioxide monomers and using a single catalyst is presented. By using a dinuclear zinc catalyst, both the ring-opening polymerization of ε-caprolactone and the ringopening copolymerization of cyclohexene oxide and carbon dioxide are achieved. The catalyst shows high selectivity, activity, and control in the ring-opening copolymerization, yielding poly(cyclohexene carbonate) polyols, i.e., α,ω-dihydroxyl end-capped polycarbonates. It also functions efficiently under immortal conditions, and in particular, the addition of various equivalents of water enables the selective preparation of polyols and control over the polymers' molecular weights and dispersities. The catalyst is also active for the ring-opening polymerization of ε-caprolactone but only in the presence of epoxide, generating α,ω-dihydroxyl-terminated polycaprolactones. It is also possible to combine the two polymerization pathways and, by controlling the chemistry of the growing polymer chain-metal end group, to direct a particular polymerization pathway. Thus, in the presence of all three monomers, the selective ring-opening copolymerization occurs to yield poly(cyclohexene carbonate). Upon removal of the carbon dioxide, the polymerization cycle switches to ring-opening polymerization and a triblock copoly(caprolactone-b-cyclohexene carbonate-b-caprolactone) is produced. The ABA type block copolymer is fully characterized, including using various spectroscopic techniques, size exclusion chromatography, and differential scanning calorimetry. The copolymers can be solvent cast to give transparent films. The copolymers show controllable glass transition temperatures from −54 to 34°C, which are dependent on the block compositions. ■ INTRODUCTIONAliphatic polycarbonates and polyesters are important polymers for both commodity and medical applications. 1−18 Combining both carbonate and ester linkages into copolymers is an attractive means to moderate macroscopic properties and widen the range of applications. In this context, block copolymers are particularly desirable due to the ability to use their chemistry and composition to precisely control the morphology on the nano-and micrometer scales. Block copolymers are useful products in fields spanning microelectronics, advanced plastics, controlled release, and engineering materials. 19−22 Recent successes from the groups of Yang and Hedrick have demonstrated the potential for aliphatic polycarbonates, and related copolymers, in a range of important biomedical applications, including as vectors for the delivery of drugs, as antimicrobial surfaces, or as materials for cell proliferation/growth. 23−33 The preparation of multiblock copolymers is best accomplished using controlled polymerization methods. In the context of polyesters and -carbonates, controlled polymerizations include the metal catalyzed ring-opening polymerization (ROP) of cyclic esters 14,34−38 or cyclic carbonates ...

Vagal, spinal and intestino-fugal fibres all potentially transmit mechanosensory afferent information from the gastrointestinal tract. We aimed to characterize the relative mechanosensitivity of these three different afferent populations supplying the rat jejunum. Afferent nerve discharge was recorded from pentobarbitone-anaesthetized rats during different distension protocols. Saline ramp distension (1 mL min(-1)) and barostat ramp distension (2 mmHg 4 s(-1)) each evoked biphasic responses but with the latter significantly attenuated especially at low distending pressures. Barostat controlled phasic distensions (10-50 mmHg, 25 s) evoked an afferent response with a peak at the onset of distension adapting to a plateau level that was maintained and comparable to the barostat ramp responses at the corresponding pressures. Chronic subdiaphragmatic vagotomy significantly attenuated the low pressure component of the response to balloon ramp distension and both peak and plateau responses to phasic distension. Single unit analysis showed an absence of low threshold afferent activity after vagotomy while the response to fibres with wide-dynamic range and high threshold sensitivity were preserved hexamethonium had no effect on the responses to either ramp or phasic distension. These findings suggest that the nature of the distension stimulus is critical in determining the pattern of response observed from the various subpopulations of afferents supplying the bowel wall.