Human immunodeficiency virus (HIV)-and simian immunodeficiency virus (SIV)-specific CD8؉ T cells are typically largely excluded from lymphoid B cell follicles, where HIV-and SIV-producing cells are most highly concentrated, indicating that B cell follicles are somewhat of an immunoprivileged site. To gain insights into virus-specific follicular CD8؉ T cells, we determined the location and phenotype of follicular SIV-specific CD8 ؉ T cells in situ, the local relationship of these cells to Foxp3 ؉ cells, and the effects of CD8 depletion on levels of follicular SIV-producing cells in chronically SIV-infected rhesus macaques. We found that follicular SIV-specific CD8 ؉ T cells were able to migrate throughout follicular areas, including germinal centers. Many expressed PD-1, indicating that they may have been exhausted. A small subset was in direct contact with and likely inhibited by Foxp3؉ cells, and a few were themselves Foxp3 ؉ . In addition, subsets of follicular SIV-specific CD8 ؉ T cells expressed low to medium levels of perforin, and subsets were activated and proliferating. Importantly, after CD8 depletion, the number of SIVproducing cells increased in B cell follicles and extrafollicular areas, suggesting that follicular and extrafollicular CD8؉ T cells have a suppressive effect on SIV replication. Taken together, these results suggest that during chronic SIV infection, despite high levels of exhaustion and likely inhibition by

Background. Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC).Patients and Methods. Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and ChildPugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary end-

The exacerbation of musculoskeletal pain by stress in humans is modeled by the musculoskeletal hyperalgesia in rodents following a forced swim. We hypothesized that stress-sensitive corticotropin releasing factor (CRF) receptors and transient receptor vanilloid 1 (TRPV1) receptors are responsible for the swim stress-induced musculoskeletal hyperalgesia. We confirmed that a cold swim (26°C) caused a transient, morphine-sensitive decrease in grip force responses reflecting musculoskeletal hyperalgesia in mice. Pretreatment with the CRF2 receptor antagonist astressin 2B, but not the CRF1 receptor antagonist NBI-35965, attenuated this hyperalgesia. Desensitizing the TRPV1 receptor centrally or peripherally using desensitizing doses of resiniferatoxin (RTX) failed to prevent the musculoskeletal hyperalgesia produced by cold swim. SB-366791, a TRPV1 antagonist, also failed to influence swim-induced hyperalgesia. Together these data indicate that swim stress-induced musculoskeletal hyperalgesia is mediated, in part, by CRF2 receptors but is independent of the TRPV1 receptor.

The CNS expresses many components of an extracellular protease signalling system, including the protease‐activated receptor‐1 (PAR‐1) whose tethered ligand is generated by thrombin. Activation of PAR‐1 potentiates NMDA receptor activity in hippocampal neurons. Because NMDA activity mediates hyperalgesia, we tested the hypothesis that PAR‐1 receptors also regulate pain processing. In contrast to the potentiating effect of thrombin in the hippocampus, NMDA‐induced behaviours and the transient mechanical hyperalgesia (von Frey fibres) induced by intrathecally injected NMDA in mice were inhibited by thrombin in a dose‐related fashion. This anti‐hyperalgesic effect was mimicked by SFLLRN, the natural ligand at PAR‐1 binding sites, but not SLIGRL‐amide, a PAR‐2 agonist. The effects of SFLLRN were less potent and shorter in duration than that of thrombin, consistent with its more transient effect on PAR‐1 sites. Both thrombin and SFLLRN inhibited acetic acid‐induced abdominal stretch (writhing) behaviours, which were also sensitive to NMDA antagonism, but not hot plate or tail flick latencies, which were insensitive to NMDA antagonists. TFLLR‐amide, a selective ligand for PAR‐1 sites, mimicked the effects of thrombin while RLLFT‐amide, an inactive, reverse peptide sequence, did not. In addition, the effect of TFLLR‐amide was prevented by RWJ‐56110, a PAR‐1 antagonist. Thrombin and TFLLR‐amide produced no oedema (Evans Blue extravasation) in the spinal cord that would account for these effects. Based on the reported ability of thrombin to mobilize endothelin‐1 from astrocytes, we tested the role of this compound in thrombin's activity. BQ123, an endothelin A receptor antagonist, prevented thrombin's inhibition of writhing and NMDA‐induced behaviours while BQ788, an endothelin B receptor antagonist, did not. Thus, activation of PAR‐1 sites by thrombin in the CNS appears to inhibit NMDA‐mediated nociception by a pathway involving endothelin type A receptors.

Single exposures to lipopolysaccharides (LPS) produce deep tissue pain in humans and cutaneous hyperalgesia in rodents. While tolerance develops to many effects of LPS, sensitization to hyperalgesia is documented after a single injection. To determine the effect of long-term exposure to LPS, we explored the chronic effect of LPS on movement-evoked pain using a new assay based on grip force in mice. We found that a single systemic injection of LPS (i.p. or s.c.) induced a dose-related decrease in forelimb grip force responses beginning 6-8 h after injection and peaking between 9 and 24 h. The consequence of LPS is likely hyperalgesia rather than weakness as these decreases were rapidly attenuated by either 10 mg/kg of morphine i.p. or 10 microg of morphine injected intrathecally (i.t.). Complete tolerance to this hyperalgesia developed after repeated injections of LPS at doses of 0.9 mg/kg i.p. or 5 mg/kg s.c. Tolerance began after a single injection and was fully developed after as few as four injections of 5 mg/kg of LPS delivered s.c. The concentration of circulating LPS 5 h after a single parenteral injection was less in LPS-tolerant mice than naïve controls, suggesting that tolerance may result from a more efficient clearance of LPS from the circulation. Injected i.t., LPS also induced hyperalgesia, however, tolerance did not develop to multiple injections by this route. There was no cross-tolerance between s.c. and i.t. injections of LPS. These data indicate that decreases in grip force are a sensitive measure of LPS-induced movement-evoked hyperalgesia and that tolerance develops to parenteral but not central hyperalgesic effects of LPS.