Selective Reduction of Post-Selection CD8 Thymocyte Proliferation in IL-15Rα Deficient Mice

Peripheral CD8+ T cells are defective in both IL-15 and IL-15Rα knock-out (KO) mice; however, whether IL-15/IL-15Rα deficiency has a similar effect on CD8 single-positive (SP) thymocytes remains unclear. In this study, we investigated whether the absence of IL-15 transpresentation in IL-15Rα KO mice results in a defect in thymic CD8 single positive (SP) TCRhi thymocytes. Comparison of CD8SP TCRhi thymocytes from IL-15Rα KO mice with their wild type (WT) counterparts by flow cytometry showed a significant reduction in the percentage of CD69− CD8SP TCRhi thymocytes, which represent thymic premigrants. In addition, analysis of in vivo 5-bromo-2-deoxyuridine (BrdU) incorporation demonstrated that premigrant expansion of CD8SP TCRhi thymocytes was reduced in IL-15Rα KO mice. The presence of IL-15 transpresentation-dependent expansion in CD8SP TCRhi thymocytes was assessed by culturing total thymocytes in IL-15Rα-Fc fusion protein-pre-bound plates that were pre-incubated with IL-15 to mimic IL-15 transpresentation in vitro. The results demonstrated that CD8SP thymocytes selectively outgrew other thymic subsets. The contribution of the newly divided CD8SP thymocytes to the peripheral CD8+ T cell pool was examined using double labeling with intrathymically injected FITC and intravenously injected BrdU. A marked decrease in FITC+ BrdU+ CD8+ T cells was observed in the IL-15Rα KO lymph nodes. Through these experiments, we identified an IL-15 transpresentation-dependent proliferation process selective for the mature CD8SP premigrant subpopulation. Importantly, this process may contribute to the maintenance of the normal peripheral CD8+ T cell pool

Rifaximin for the treatment of acute infectious diarrhea

Rifaximin is a nonabsorbable rifamycin derivative with an excellent safety profile and a broad spectrum of antimicrobial activity against a variety of enteropathogens causing acute infectious diarrhea. After oral ingestion, its bioavailability is known to be less than 0.4%, and it has a low potential for significant drug interactions. In the treatment of travelers’ diarrhea caused by noninvasive diarrheagenic Escherichia coli, it has been demonstrated that rifaximin significantly shortens the duration of diarrhea and has an efficacy similar to that of ciprofloxacin. Moreover, according to two randomized placebo-controlled trials, prophylactic treatment with rifaximin reduced the risk of developing travelers’ diarrhea by more than 50% compared with the placebo group. For the treatment of acute diarrhea unrelated to travel, a short course of rifaximin significantly reduced the duration of diarrhea, and its overall efficacy was comparable to that of ciprofloxacin. The discrepancy between the in vitro and in vivoantimicrobial activities of rifaximin, however, and the clinical implication of the rapid appearance of bacterial resistance, must be further elucidated. In conclusion, this gut-selective antibiotic seems to be a promising option for the treatment of acute infectious diarrhea secondary to noninvasive E. coli and also appears to be effective in chemoprophylaxis for travelers’ diarrhea

Tumor Microenvironment Conditioning by Abortive Lytic Replication of Oncogenic γ-Herpesviruses

Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) constitute the human γ-herpesviruses and two of the seven human tumor viruses. In addition to their viral oncogenes that primarily belong to the latent infection programs of these viruses, they encode proteins that condition the microenvironment. Many of these are early lytic gene products and are only expressed in a subset of infected cells of the tumor mass. In this chapter I will describe their function and the evidence that targeting them in addition to the latent oncogenes could be beneficial for the treatment of EBV- and KSHV-associated malignancies

Sulodexide versus calcium heparin in the medium-term treatment of deep vein thrombosis of the lower limbs.

Thirty adult patients with distal, monolateral deep vein thrombosis of the lower limbs were randomly treated for sixty days either with subcutaneous Ca-Heparin or with Sulodexide, administered IM for ten days and orally for fifty days. The thrombus accretion above the knee, the venous pressures of the affected leg, the clinical symptomatology, and some laboratory coagulative tests were monitored throughout the administration period. Local tolerability of the two treatments was also evaluated. The two applied treatments evidenced a net antithrombotic activity, preventing thrombus accretion above the knee, improving with the same efficacy the venous pressures in the affected legs, and similarly reducing clinical symptoms, with a quick and statistically significant trend toward normalization. Blood fibrinogen was significantly lowered by both drugs, while only Ca-heparin yielded a prolongation of activated partial thromboplastin time. Local tolerability of treatments was better for the mainly oral Sulodexide administrations, while subcutaneous Ca-heparin often induced small, though transient, hematom

Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions

Chemokines and their G-protein-coupled receptors represent an ancient and complex system of cellular communication participating in growth, development, homeostasis and immunity. Chemokine production has been detected in virtually every microbial infection examined; however, the precise role of chemokines is still far from clear. In most cases they appear to promote host resistance by mobilizing leukocytes and activating immune functions that kill, expel, or sequester pathogens. In other cases, the chemokine system has been pirated by pathogens, especially protozoa and viruses, which have exploited host chemokine receptors as modes of cellular invasion or developed chemokine mimics and binding proteins that act as antagonists or inappropriate agonists. Understanding microbial mechanisms of chemokine evasion will potentially lead to novel antimicrobial and anti-inflammatory therapeutic agents