Triple-combination antiviral drug for pandemic H1N1 influenza virus infection in critically ill patients on mechanical ventilation

A recent in vitro study showed that the three compounds of antiviral drugs with different mechanisms of action (amantadine, ribavirin, and oseltamivir) could result in synergistic antiviral activity against influenza virus. However, no clinical studies have evaluated the efficacy and safety of combination antiviral therapy in patients with severe influenza illness. A total of 245 adult patients who were critically ill with confirmed pandemic influenza A/H1N1 2009 (pH1N1) virus infection and were admitted to one of the intensive care units of 28 hospitals in Korea were reviewed. Patients who required ventilator support and received either triple-combination antiviral drug (TCAD) therapy or oseltamivir monotherapy were analyzed. A total of 127 patients were included in our analysis. Among them, 24 patients received TCAD therapy, and 103 patients received oseltamivir monotherapy. The 14-day mortality was 17% in the TCAD group and 35% in the oseltamivir group (P = 0.08), and the 90-day mortality was 46% in the TCAD group and 59% in the oseltamivir group (P = 0.23). None of the toxicities attributable to antiviral drugs occurred in either group of our study, including hemolytic anemia and hepatic toxicities related to the use of ribavirin. Logistic regression analysis indicated that the odds ratio for the association of TCAD with 90-day mortality was 0.58 (95% confidence interval, 0.24 to 1.42; P = 0.24). Although this study was retrospective and did not provide virologic outcomes, our results suggest that the treatment outcome of the triple combination of amantadine, ribavirin, and oseltamivir was comparable to that of oseltamivir monotherapy.     

Elevated expression of interleukin‐7 receptor in inflamed joints mediates interleukin‐7–induced immune activation in rheumatoid arthritis

Objective

To evaluate the expression and functional ability of the high‐affinity interleukin‐7 receptor (IL‐7Rα) in patients with rheumatoid arthritis (RA).

Methods

Expression of IL‐7Rα and IL‐7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL‐7Rα expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL‐7Rα^bright and IL‐7Rα^dim/− T cells was measured. In addition, we examined IL‐7R blockade with soluble human IL‐7Rα (hIL‐7Rα) in the prevention of immune activation of peripheral blood mononuclear cells.

Results

We found significantly higher IL‐7Rα expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL‐7Rα expression correlated significantly with the levels of CD3 and IL‐7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL‐7Rα. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL‐7Rα, although less prominently than T cells. We found that peripheral blood IL‐7Rα^bright T cells that did not express FoxP3 were highly proliferative as compared with IL‐7Rα^dim/− T cells that did express high levels of FoxP3. Soluble hIL‐7Rα inhibited IL‐7–induced proliferation and interferon‐γ production by mononuclear cells from RA patients.

Conclusion

Our data suggest that enhanced expression of IL‐7Rα and IL‐7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL‐7R–mediated immune activation by soluble hIL‐7Rα further indicates an important role of IL‐7Rα in inflammatory responses in RA, suggesting IL‐7Rα as a therapeutic target for immunotherapy in RA.

     

The combination of the biomarkers urinary C‐terminal telopeptide of type II collagen,serum cartilage oligomeric matrix protein,and serum chondroitin sulfate 846 reflects cartilage damage in hemophilic arthropathy

Objective

Hemophilic arthropathy, with characteristics of inflammatory (rheumatoid arthritis) and degenerative (osteoarthritis) joint damage, occurs at an early age, is associated with minor comorbidity, and is restricted to 3 pairs of large joints. The aim of this study was to determine whether commonly used serum and/or urinary biomarkers of cartilage and bone turnover for which assay kits are commercially available are associated with the severity of joint damage in patients with various degrees of hemophilic arthropathy and, thus, whether this disease could be useful in the identification and evaluation of such biomarkers.

Methods

Blood and urine samples were collected from 36 patients with various degrees of hemophilic arthropathy. Commercially available assays for the most frequently investigated serum and urine biomarkers were performed: urinary C‐terminal telopeptide of type I collagen (CTX‐I), urinary CTX‐II, serum CTX‐I, serum CTX‐II, serum cartilage oligomeric matrix protein (COMP), serum cartilage cleavage products C1,2C and C2C, and serum chondroitin sulfate 846 (CS‐846). Radiographs of the ankles, knees, and elbows in all patients were evaluated for the degree of joint damage according to the Pettersson score, which is based on cartilage and periarticular bone changes and is specific for hemophilic arthropathy.

Results

Urinary CTX‐II, serum C1,2C, and serum CS‐846 levels correlated with the overall Pettersson score and with the joint space narrowing component. Regression analysis showed that combined indexes of different markers increased the degree of correlation for the combination of urinary CTX‐II, serum COMP, and serum CS‐846. Bone‐specific markers (urinary/serum CTX‐I and serum C1,2C) did not correlate with specific bone‐related items of the Pettersson score (osteoporosis and erosions).

Conclusion

These results support the idea that a combination of biomarkers relates significantly better to the severity of joint damage than do individual biomarkers. The combination of urinary CTX‐II, serum COMP, and serum CS‐846 correlated best with the degree of arthropathy. Because of its specific characteristics and restricted involvement, hemophilic arthropathy may prove useful in the screening of newly developed biomarkers of joint damage.

     

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

Objective

Human Hsp60 is expressed in the joints of patients with rheumatoid arthritis (RA) and can elicit a regulatory T cell response in the peripheral blood and synovial fluid. However, Hsp60 can also trigger strong proinflammatory pathways. Thus, to understand the nature of these Hsp60‐directed responses in RA, it is necessary to study such responses at the molecular, epitope‐specific level. This study was undertaken to characterize the disease specificity and function of pan–DR‐binding Hsp60–derived epitopes as possible modulators of autoimmune inflammation in RA.

Methods

Lymphocyte proliferation assays (using ³H‐thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester [CFSE] staining) and measurement of cytokine production (using multiplex immunoassay and intracellular staining) were performed after in vitro activation of peripheral blood mononuclear cells from patients with RA, compared with healthy controls.

Results

A disease (RA)–specific immune recognition, characterized by T cell proliferation as well as increased production of tumor necrosis factor α (TNFα), interleukin‐1β (IL‐1β), and IL‐10, was found for 3 of the 8 selected peptides in patients with RA as compared with healthy controls (P < 0.05). Intracellular cytokine staining and CFSE labeling showed that CD4+ T cells were the subset primarily responsible for both the T cell proliferation and the cytokine production in RA. Interestingly, the human peptides had a remarkably different phenotype, with a 5–10‐fold higher IL‐10:TNFα ratio, compared with that of the microbial peptides.

Conclusion

These results suggest a disease‐specific immune‐modulatory role of epitope‐specific T cells in the inflammatory processes of RA. Therefore, these pan–DR‐binding epitopes could be used as a tool to study the autoreactive T cell response in RA and might be suitable candidates for use in immunotherapy.

     

Radiation synovectomy with yttrium-90 for persisting arthritis has direct harmful effects on human cartilage that cannot be prevented by co-administration of glucocorticoids: an in vitro study

BACKGROUND: It was recently shown that radiation synovectomy with yttrium-90 (90Y) and glucocorticoids is not superior to intra-articular glucocorticoids alone in the treatment of persistent gonarthritis. In that study, it seemed that in patients treated by radiation synovectomy, progression of radiographic joint damage occurred. OBJECTIVE: To test in vitro the direct effects of radiation synovectomy with 90Y on human cartilage. METHODS: Human cartilage tissue was exposed to 90Y, glucocorticoids or the combination. 1:2000 to 1:20 dilutions of the clinical dose of 5 mCi/ml 90Y and 20 mg/ml glucocorticoids were used. After a 4-day exposure and a subsequent 12-day recovery period, proteoglycan synthesis, proteoglycan release and proteoglycan content were measured. In addition, human synovial tissue was cultured for 4 days with 90Y or glucocorticoids. Culture supernatants were analysed for cartilage-destructive activity. RESULTS: 90Y, glucocorticoids and the combination inhibited proteoglycan synthesis considerably and dose dependently, an effect that sustained for at least 12 days. Proteoglycan release was transiently increased by 90Y, an effect that was not changed by addition of glucocorticoids, which had no effect on its own. Proteoglycan content was eventually adversely affected by 90Y, an effect hardly influenced by glucocorticoids. Neither 90Y nor glucocorticoids changed the cartilage-destructive properties of synovial tissue. CONCLUSIONS: 90Y, but not glucocorticoids, has direct harmful effects on cartilage in vitro. Indirect beneficial effects of 90Y via inhibition of cartilage-destructive properties of synovial tissue could not be shown. These observations may explain the possible radiographic joint damage on radiation synovectomy.     

Anticancer activity of essential oils and their chemical components - a review

Essential oils are widely used in pharmaceutical, sanitary, cosmetic, agriculture and food industries for their bactericidal, virucidal, fungicidal, antiparasitical and insecticidal properties. Their anticancer activity is well documented. Over a hundred essential oils from more than twenty plant families have been tested on more than twenty types of cancers in last past ten years. This review is focused on the activity of essential oils and their components on various types of cancers. For some of them the mechanisms involved in their anticancer activities have been carried out.