Prognostic factors of patients requiring prolonged mechanical ventilation in a medical intensive care unit of Korea.

BACKGROUND: We evaluated the clinical outcomes and prognostic factors of patients requiring prolonged mechanical ventilation (PMV), defined as ventilator care for ≥21 days, who were admitted to the medical intensive care unit (ICU) of a university hospital in Korea. METHODS: During the study period, a total of 2,644 patients were admitted to the medical ICU, and 136 patients (5.1%) were enrolled between 2005 and 2010. RESULTS: The mean age of the patients was 61.3±14.5 years, and 94 (69.1%) were male. The ICU and six-month cumulative mortality rates were 45.6 and 58.8%, respectively. There were 96 patients with tracheostomy placement after admission and their mean period from admission to the day of tracheostomy was 21.3±8.4 days. Sixty-three patients (46.3%) were successfully weaned from ventilator care. Of the ICU survivors (n=74), 34 patients (45.9%) were transferred to other hospitals (not university hospitals). Two variables (thrombocytopenia [hazard ratio (HR), 1.964; 95% confidence interval (CI), 1.225~3.148; p=0.005] and the requirement for vasopressors [HR, 1.822; 95% CI, 1.111~2.986; p=0.017] on day 21) were found to be independent factors of survival on based on the Cox proportional hazard model. CONCLUSION: We found that patients requiring PMV had high six-month cumulative mortality rates, and that two clinical variables (measured on day 21), thrombocytopenia and requirement for vasopressors, may be associated with prognostic indicators.

Macrophage migration inhibitory factor isolated from a parasite inhibited Th2 cytokine production in PBMCs of atopic asthma patients.

BACKGROUND: In a previous study, we demonstrated that the human macrophage migration inhibitory factor (MIF)-like protein (As-MIF) isolated from helminths could inhibit allergic airway inflammation via the recruitment of CD4(+)CD25(+)Foxp3(+) T cells. OBJECTIVE: To evaluate the clinical importance of As-MIF as an antiasthma drug, we evaluated immune responses after recombinant As-MIF (rAs-MIF) treatment in peripheral blood mononuclear cell (PBMC) cultures. METHODS: PBMC was isolated from 10 patients with atopic asthma, 8 patients with nonatopic asthma, and 12 nonatopic healthy subjects, and various concentrations of rAs-MIF were transferred into the PBMC culture medium. After 3 days, we measured the levels of T helper 2 and T helper 1 cytokines via ELISA. RESULTS: In atopic asthma, IL-4 and IL-5 production was significantly reduced in the PBMC cultures after rAs-MIF treatment. These inhibitory effects were not observed in the nonatopic asthma group. By way of contrast, IL-10 production in the PMBC cultures was significantly increased after rAs-MIF treatment in all experimental groups. CONCLUSION: The results of this study are similar to those previously reported in a mouse study, suggesting that As-MIF might be a candidate for the specific treatment of asthma.

Outcome of pandemic H1N1 pneumonia: clinical and radiological findings for severity assessment.

BACKGROUND/AIMS: Pandemic influenza A (H1N1) virus infection presents with variable severity. However, little is known about clinical predictors of disease severity. We studied the clinical predictors of severe pandemic H1N1 pneumonia and their correlation with radiological findings. METHODS: We reviewed medical and radiological records of adults with pandemic H1N1 pneumonia. After classification of patients into severe and non-severe groups, the following data were evaluated: demographic data, pneumonia severity index (PSI), CURB65, risk factors, time to first dose of antiviral medication, routine laboratory data, clinical outcome, and radiological characteristics. RESULTS: Of 37 patients with pandemic H1N1 pneumonia, 12 and 25 were assigned to the severe and non-severe groups, respectively. PSI score, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dyhydrogenase (LDH) levels were higher in the severe group than in the non-severe group (p = 0.035, 0.0003, 0.0023, and 0.0002, respectively). AST, ALT, and LDH levels were positively correlated with the radiological findings (p < 0.0001, 0.0003, and < 0.0001, respectively) and with the number of involved lobes (p = 0.663, 0.0134, and 0.0019, respectively). The most common finding on high resolution computed tomography (HRCT) scans was ground-glass attenuation with consolidation (n = 22, 60%), which had a predominantly patchy distribution (n = 31). CONCLUSIONS: We demonstrated a positive correlation between clinical findings, such as serum AST, ALT, and LDH levels, and radiological findings. A combination of clinical and HRCT indicators would be useful in predicting the clinical outcome of pandemic H1N1 pneumonia.

Adipose-derived stromal cells inhibit allergic airway inflammation in mice.

Allergic asthma is an inflammatory airway disease caused by T helper type 2 (Th2)-driven immune responses. Recent studies have demonstrated that adipose-derived stromal cells (ASC) have an immunosuppressive effect on T-cell activity. This study was performed to investigate whether ASC can inhibit Th2-dependent allergic airway inflammation in mice. BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injection. To investigate the effect of ASC on the development of asthma phenotypes, 2 × 106 ASC were injected intravenously before OVA challenge. We evaluated the airway hyperresponsiveness (AHR), the proportion of eosinophils and cytokine production in bronchoalveolar lavage fluid (BALF), airway inflammation, and the intracellular cytokine staining of T cells in the BALF and spleen. Airway hyperresponsiveness, airway eosinophilia, and mucus production were markedly reduced after ASC administration before OVA challenge. The increased interleukin (IL)-4, IL-5, and transforming growth factor (TGF)-ß1 levels in the BALF after OVA challenge were significantly reduced by the administration of ASC. This inhibition was accompanied by decreased IL-4(+) CD4(+) T cells and increased interferon (IFN)-γ(+) CD4(+) T cells in the BALF and spleen. The results of this study suggest that ASC administration before an allergen challenge inhibits AHR, lung inflammation, and Th2 cytokine production induced by an allergen challenge through inhibition of Th2 cell activity.

Comparison of the clinical efficacy and safety of salmeterol/fluticasone propionate versus current care in the management of persistent asthma in Korea.

OBJECTIVES: In the Asia-Pacific region there is a general preference for prescribing oral over inhaled medications for the treatment of asthma. This study compared inhaled salmeterol/fluticasone propionate therapy (SFC) with physician-determined current care (CC) in the management of persistent asthma in Korea. METHODS: Adult patients with a documented history of reversibility in FEV(1) (>or= 12%) or PEF (>or= 15%), were randomised in a 2:1 ratio to unblinded treatment with SFC (50/250 microg bd or 50/500 microg bd) via Diskus (N = 284) or CC (N = 140) for 52 weeks. Morning peak expiratory flow (PEF) (primary endpoint), exacerbations, asthma symptoms and patient-reported outcome measures were recorded. TRIAL REGISTRATION: GSK study number:100614. RESULTS: At baseline, mean morning PEF in the SFC and CC group was 374 and 401 L/min respectively. The adjusted mean morning PEF at 52 weeks was 423 +/- 3 and 396 +/- 4 L/min for SFC and CC respectively (treatment difference of 27 +/- 5 in favour of SFC; 95% CI 17, 37; p < 0.0001). The mean rate of exacerbations over 52 weeks was significantly lower in the SFC group (SFC/CC odds ratio 0.57; 95% CI 0.44, 0.74; p < 0.0001). Treatment with SFC also resulted in a significantly greater improvement in asthma symptoms, in the number of patients assessed to have well controlled asthma (Asthma Control Test score >or= 20), and in a clinically significant improvement in overall Quality of Life. The incidence of adverse events was low and similar between the two groups and events were of the type expected in this population. CONCLUSIONS: The results of this open-label, randomised study showed that SFC provided greater asthma control than CC in the management of persistent asthma.

Air-liquid interface culture of serially passaged human nasal epithelial cell monolayer for in vitro drug transport studies.

The objective of this study was to establish a drug transport study using human nasal epithelial (HNE) cell monolayers cultured by the air-liquid interface (ALI) method using serum-free medium (BEGM:DME/F12, 50:50). The cells were developed and characterized in comparison to those that have been previously cultured by the liquid-covered culture (LCC) method. The epithelial cell monolayer cultured by the ALI method resulted in a significantly higher transepithelial electrical resistance value (3,453 +/- 302 ohm x cm(2)) that was maintained (>1,000 ohm x cm(2)) for up to 20 days compared with that cultured by the LCC method. Observation by scanning electron microscopy revealed mature cilia after 2 weeks in the ALI culture, while flatten unhealthy ciliated cells were observed in the LCC method. After 21 days, higher level of MUC5AC and 8 mRNA were expressed in ALI culture which confirmed the secretory differentiation of HNE monolayers in vitro. No significant difference in the permeability coefficients of a model hydrophilic marker ((14)C-mannitol) and a lipophilic drug (budesonide) was observed between the two conditions on day 7. The passage 2-3 of the HNE monolayer using ALI condition retained the morphology and differentiated features of normal epithelium. Thus it would be a suitable model for in vitro nasal drug delivery studies.

Acidic polysaccharides isolated from Phellinus linteus induce phenotypic and functional maturation of murine dendritic cells.

Acidic polysaccharides (PL) isolated from Phellinus linteus are known to stimulate the proliferation of T lymphocytes and humoral immune functions to act as a polyclonal activator of B cells, and to inhibit tumor growth and metastasis. However, little is known about their immunomodulating effects or the effects of its mechanisms on murine bone marrow (BM)-derived dendritic cells (DC). In this study, it profoundly increased CD80, CD86, MHC I, and MHC II expression in murine, GM-CSF and IL-4 stimulated, BM-derived myeloid DC. The ability of unstimulated DC to uptake dextran was higher than that of PL- or LPS-stimulated DC. We analyzed the concentration of IL-12 secreted by DC using flow cytometry and ELISA. Untreated DC secreted a low concentration of IL-12, while PL- or LPS-stimulated DC secreted higher levels of IL-12 than untreated DC. There were no remarkable differences in the concentrations of IL-12 produced by PL- or LPS-stimulated DC. However, polymyxin B (PB; an LPS inhibitor) effectively inhibited the surface molecules and IL-12 production induced by LPS, but had no effect on the PL in DC. PL-treated DC were much more potent antigen-presenting cells in allogeneic immune response than untreated DC. PL treatment not only formed morphologically mature DC but also induced predominant migration to lymphoid tissues. Moreover, the inhibitors of protein tyrosine kinase (PTK) or protein kinase C (PKC) significantly blocked the expression of surface molecules and IL-12 production in PL-stimulated DC. Treatment of DC with PL directly induced PKC activity and phosphorylated PTK. Furthermore, CD11b and/or CD18 partially mediated PL-induced DC maturation.

Alleviation of experimental septic shock in mice by acidic polysaccharide isolated from the medicinal mushroom Phellinus linteus.

This study reports that acidic polysaccharide (PL) isolated from Phellinus linteus alleviated the septic shock induced by high dose lipopolysaccharide (LPS) injection in mice. To examine the origin of this effect, we investigated cytokine production in serum and the expression of MHC II in B cells and macrophages in areas of inflammation. Pretreatment with PL 24 h before LPS administration resulted in a significant inhibition of up to 68% of circulating tumor necrosis factor (TNF)-alpha, a moderate reduction of 45% of interleukine (IL)-12 and 23% of IL-1beta, but no significant reduction in IL-6. In addition, the expression of MHC II in B cells and macrophages was examined. Our results show that LPS-stimulated cytokine release and the level of MHC II can be modulated by in vivo administration of soluble PL in mice. The decrease of IL-1beta, IL-12 and TNF-alpha in sera and the down-modulation of MHC II during septic shock may contribute to the long survival of mice by PL. Administration of PL in vivo decreases IL-2, IFN-gamma and TNF-alpha production in splencotyes and enhances spontaneous cell apoptosis in macrophages and lymphocytes stimulated with LPS in vitro. Thus, part of the anti-inflammatory effects of PL treatment in vivo may result from the enhanced apoptosis of a portion of the activated macrophages and lymphocytes. The ability of PL to significantly reduce the TNF-alpha production indicates the potential of the polysaccharides in possible therapeutic strategies that are based on down-regulation of TNF-alpha.

Proteoglycan isolated from Phellinus linteus activates murine B lymphocytes via protein kinase C and protein tyrosine kinase.

Medicinal mushrooms are increasingly used to treat a wide variety of disease processes. Aqueous extract from the fruiting body or mycelia of Phellinus linteus has been reported to produce antitumor and immunomodulatory activities in vivo and in vitro. However, the therapeutic mechanism has not been known. In the present study, we investigated whether proteoglycan (PL) isolated from P. linteus has an effect on the immunomodulatory activities of the murine splenic lymphocytes (MSLs). Treatment with PL caused a four-fold augmentation in [3H]thymidine incorporation compared to untreated control group in MSLs. Flow cytometric analysis indicated that the affected cell population was mainly CD19(+) cells, but not CD3(+) cells. These data suggested that the main target of PL was the B cells, but not T cells. PL also enhanced the expression of co-stimulatory molecules, CD80 and CD86, in murine B cells in a time-dependent manner. Accordingly, we investigated if intracellular [Ca(2+)] and reactive oxygen intermediates (ROI) were the principal downstream components that contributed to PL-induced activation, with respect to both increases of proliferation and induction of co-stimulatory molecules. However, PL has no influence on the [Ca(2+)] concentration and the ROI formation in murine B cells, whereas the genistein, protein tyrosine kinase (PTK) inhibitor or staurosporine, protein kinase C (PKC), blocked the proliferation and the induction of co-stimulatory molecules, CD80 and CD86, in B cells stimulated with PL. Taken together, these data suggest that PL is a biological response modifier that stimulates proliferation and expression of co-stimulatory molecules in B cells, probably by regulating PTK and PKC signaling pathways.

Oral administration of proteoglycan isolated from Phellinus linteus in the prevention and treatment of collagen-induced arthritis in mice.

To examine whether oral administration of proteoglycan derived from Phellinus linteus, which is known as the medicinal mushroom, can prevent or treat collagen-induced arthritis (CIA) in mice as experimental model of autoimmune disease. CIA was induced by intradermal injection of type II collagen (CII) emulsified with complete freund's adjuvant (CFA) into the base of the tail (on day 7) followed by a booster injection on day 21 into the footpad. To examine the ability of proteoglycan to effect the inhibition of CIA, doses of proteoglycan were orally administered on day 0 (pre-administration) or day 28 (post-administration) at two groups. The inhibition of CIA by oral administration of proteoglycan was associated with decrease in anti-CII IgG and IgG2a antibodies (Abs) as well as varying kinds of cytokines including IL-12, TNF-alpha, and IFN-gamma. The results showed that administration of proteoglycan was followed by decrease of CIA of the mice in pre- and post-administration groups. Our findings suggest that immunomodulating proteoglycan isolated from P. linteus may be crucially involved in the prevention and treatment of autoimmune joint inflammation such as rheumatoid arthritis, although no definite role of anti-CII Abs in the human disease has been established.