Aberrant inflammatory response to Streptococcus pyogenes in mice lacking myeloid differentiation factor 88.
ABSTRACT Several in vitro studies have emphasized the importance of toll-like receptor/myeloid differentiation factor 88 (MyD88) signaling in the inflammatory response to Streptococcus pyogenes. Since the extent of inflammation has been implicated in the severity of streptococcal diseases, we have examined here the role of toll-like receptor/MyD88 signaling in the pathophysiology of experimental S. pyogenes infection. To this end, we compared the response of MyD88-knockout (MyD88(-/-)) after subcutaneous inoculation with S. pyogenes with that of C57BL/6 mice. Our results show that MyD88(-/-) mice harbored significantly more bacteria in the organs and succumbed to infection much earlier than C57BL/6 animals. Absence of MyD88 resulted in diminished production of inflammatory cytokines such as interleukin-12, interferon-gamma, and tumor necrosis factor-alpha as well as chemoattractants such as monocyte chemotactic protein-1 (MCP-1) and Keratinocyte-derived chemokine (KC), and hampered recruitment of effector cells involved in bacterial clearance (macrophages and neutrophils) to the infection site. Furthermore, MyD88(-/-) but not C57BL/6 mice exhibited a massive infiltration of eosinophils in infected organs, which can be explained by an impaired production of the regulatory chemokines, gamma interferon-induced monokine (MIG/CXCL9) and interferon-induced protein 10 (IP-10/CXCL10), which can inhibit transmigration of eosinophils. Our results indicate that MyD88 signaling targets effector cells to the site of streptococcal infection and prevents extravasation of cells that can induce tissue damage. Therefore, MyD88 signaling may be important for shaping the quality of the inflammatory response elicited during infection to ensure optimal effector functions.
Article: Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats.[show abstract] [hide abstract]
ABSTRACT: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking. Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test. The orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test. The results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.Psychopharmacologia 08/2008; 199(1):109-17. · 4.08 Impact Factor
Article: Effects of weekly paclitaxel or paclitaxel plus carboplatin on functionality and symptoms of geriatric patients with cancer as measured by a brief geriatric oncology module: a pilot experience.[show abstract] [hide abstract]
ABSTRACT: To measure functionality, symptoms, and quality of life in elderly patients, a geriatric oncology module (GOM) was developed that could be rapidly and effectively administered in community oncology practices. The GOM was validated by semi structured patient interviews. The authors tested 26 patients receiving chemotherapy with paclitaxel or paclitaxel plus carboplatin to determine the effect of drug treatment on functionality, symptoms, and quality of life (QOL). Chemotherapy stabilized or improved functionality, symptoms, and QOL in 75%, 86%, and 76% of patients, respectively. This GOM was easily implemented in a busy community oncology practice. Weekly paclitaxel and paclitaxel plus carboplatin produced measurable palliation in geriatric oncology patients. This GOM may be useful in the assessment of specific chemotherapeutic interventions in elderly patients with cancer in community oncology practices.Cancer 07/2005; 103(12):2623-8. · 4.77 Impact Factor