Interleukin-1-induced leukocyte extravasation across rat mesenteric microvessels is mediated by platelet-activating factor

Although our understanding of the molecular interactions that mediate the adhesion of leukocytes to venular endothelial cells has greatly expanded, very little is known about the mechanisms that mediate the passage of leukocytes across the vessel wall in vivo. The aim of the present study was to investigate the role of endogenously formed platelet-activating factor (PAF) in the process of leukocyte extravasation induced by interleukin-1 (IL-1). To determine at which stage of emigration PAF was involved, we studied the behavior of leukocytes within rat mesenteric microvessels by intravital microscopy. Rats were injected intraperitoneally with saline, recombinant rat IL-1 beta (IL-1 beta), or the peptide N-formyl-methionyl-leucyl- phenylalanine (FMLP) 4 hours before the exteriorization of the mesenteric tissue. In animals treated with IL-1 beta there was a significant increase in the number of rolling and adherent leukocytes within venules (20- to 40-micron diameter) and in the number of extravasated leukocytes in the tissue. Pretreatment of rats with the PAF receptor antagonist UK-74,505 had no effect on the leukocyte responses of rolling and adhesion, but significantly inhibited the migration of the leukocytes across the vessel wall induced by IL-1 beta (76% inhibition). A structurally unrelated PAF antagonist, WEB-2170, produced the same effect (64% inhibition). However, in contrast, UK- 74,505 had no effect on the leukocyte extravasation induced by FMLP, indicating selectivity for the response elicited by certain mediators. These results provide the first line of direct evidence for the involvement of endogenously formed PAF in the process of leukocyte extravasation induced by IL-1 in vivo.     

Hydrogen peroxide contrast echocardiography

Several agents are used as echocardiographic contrast agents, but their unreliability discourages routine clinical use. Studies from the early 1960s suggest that dilute hydrogen peroxide (H₂O₂) is a safe intravascular agent. Its use was evaluated in contrast echocardiography. To obtain dense opacification reliably, H₂O₂ (3%) was passed through a sterile 0.2 μ Millipore filter and diluted with heparinized saline solution to make a 0.1 to 0.2% solution. A drop of blood was withdrawn from an indwelling peripheral venous needle into a syringe containing 0.5 to 2.0 ml of the dilute H₂O₂ and the contents injected. Studies in dogs, normal adults and 36 patients with noncyanotic congenital and acquired cardiac disorders produced dense opacification with no complications. In vitro mixture of H₂O₂ (0.3%) with leukocyte-poor blood or plasma produced only a few microbubbles, while addition to whole blood or buffy coat produced many, suggesting a role for leukocyte peroxidase. H₂O₂ contrast echocardiography is simple, inexpensive, and reliably provides dense, sustained opacification. This study and previous studies suggest that intravenous injection of 0.2% H₂O₂ can be done safely. Great caution should be exercised in patients with severe pulmonary hypertension or large right-to-left shunts because little clinical experience with H₂O₂ is available.     

The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications

The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.     

Expression of CD27 and its ligand, CD70, on chronic lymphocytic leukemia B cells

Crosslinking the CD27 antigen on T cells provides a costimulatory signal that, in concert with T-cell receptor crosslinking, can induce T- cell proliferation and cellular immune activation. We find that chronic lymphocytic leukemia (CLL) B cells from most patients coexpress both membrane-bound and soluble CD27, along with its newly identified ligand, CD70. The expression of soluble CD27 may preclude leukemic B cells from stimulating T cells via CD70, thereby potentially impairing their ability to function as effective antigen-presenting cells. We find that leukemic B-cell expression of soluble and membrane-bound CD27 can be downmodulated through a CD40-dependent signal. This signal also induces enhanced expression of CD70 on both normal and leukemic B cells. We find that tumor necrosis factor (TNF)-alpha, or the Th1 cytokine interferon (IFN)-gamma, also can induce downmodulation of CD27, whereas Th2-associated cytokines interleukin-4 (IL-4) or IL-10 can enhance leukemic B-cell expression of this accessory molecule. The modulation of CD27 induced by these conditions is accompanied by reciprocal changes in the expression levels of CD70, suggesting that these accessory molecules may be engaged in reciprocal receptor-ligand downmodulation. Consistent with this, we observe that co-culture of CLL B cells with transfected murine plasmacytoma cells that express human CD70 affects downmodulation of CD27 and enhanced expression of CD70 on leukemic B cells, but does not affect expression of CD27 mRNA. However, we find that CD40-crosslinking, in addition to reducing the level of CD27 protein, also reduces leukemic B-cell expression of CD27 mRNA. This argues that the changes in the expression levels of CD27 following CD40-signaling are not simply due to induced increases in the expression levels of CD70. Finally, we demonstrate that reciprocal changes in expression of CD27 and CD70 may contribute to the enhanced antigen-presenting capacity of CLL B cells after CD40-dependent leukemic B-cell activation. These findings expand the understanding of the regulation of costimulatory molecules important in antigen presentation and also have implications for the immunobiology of and therapy for CLL.     

A randomized,double-blind,placebo-controlled trial of dexamethasone in severe respiratory syncytial virus (RSV) infection: effects on RSV quantity and clinical outcome

Forty-one previously healthy children <2 years of age who required mechanical ventilation for respiratory syncytial virus (RSV) infection were randomized to receive dexamethasone (0.5 mg/kg; n=22) or saline placebo (n=19) intravenously every 12 h for 4 days. RSV quantity was measured by quantitative plaque assay in fresh tracheal and nasal aspirates obtained at intervals of 24+/-3 h on days 0, 1, 2, 5, and 7 following entry. Analysis by linear mixed-effects modeling demonstrated a significantly greater decline in mean tracheal RSV quantity in the placebo group than in the dexamethasone group from day 0 to day 1 (0.82 vs. 0.21 log pfu/mL; P=.01) and from day 0 to day 2 (1.45 vs. 0.53 log pfu/mL; P=.03). No differences were found between groups in nasal RSV quantity, white blood cell counts in tracheal or nasal aspirates, serum neutralizing antibody titers during convalescence, or duration of mechanical ventilation, intensive care unit stay, or hospital stay.     

A comparison between a conventional and a fiberoptic flow-directed thermal dilution pulmonary artery catheter in critically ill patients

Invasive hemodynamic monitoring is frequently required in the management of patients in intensive care units. A fiberoptic flow-directed thermal dilution pulmonary artery catheter capable of continuously monitoring the mixed venous saturation, while more expensive than a conventional pulmonary artery catheter, theoretically could result in better patient care, and might be cost-effective if it resulted either in fewer blood tests being ordered or in less time in the intensive care unit. To test this hypothesis, we designed a randomized trial in our Medical Intensive Care Unit to compare a standard pulmonary artery catheter with a fiberoptic catheter. Twenty-six patients received a standard catheter and 25 patients received the fiberoptic catheter. There were no statistical differences between the groups in age, time in the intensive care unit, number of tests ordered, hours of mechanical ventilator therapy, hours of vasoactive drug therapy, or mortality rate. The only statistically significant differences between the groups were that (1) the fiberoptic catheter required a longer insertion time and (2) there were more technical problems in consistently obtaining the wedge pressure in the patients with the fiberoptic catheters. We conclude that routine substitution of a fiberoptic catheter for the standard pulmonary artery catheter is not indicated.