A novel scoring system to predict delirium and its relationship with the clinical course in patients with acute decompensated heart failure.

BACKGROUND: Delirium is known to be a poor prognostic factor in patients with acute decompensated heart failure (ADHF). The purpose of this study was to determine predictors of delirium on admission of ADHF patients, and to establish a scoring formula to identify patients at high risk for delirium. METHODS AND RESULTS: We recorded the Intensive Care Delirium Screening Checklist (ICDSC) score in 120 ADHF patients during their stay in the coronary care unit (CCU). Patients with a highest ICDSC score of 4 or more were diagnosed with delirium. We examined independent candidate predictors of delirium using multivariate logistic regression analysis and developed the following scoring formula, the delirium prediction score (DPS), using independent predictors of delirium and their regression coefficients: DPS=inferior vena cava diameter+C-reactive protein (and additionally +10 for patients with a history of cerebral infarction). Receiver operating curve analysis indicated that evaluation using this scoring system at the time of admission was able to predict delirium with high accuracy (C-statistic: 0.885). In addition, the calculated scores had significantly positive correlations with duration of CCU stay and overall length of hospital stay. CONCLUSIONS: We established a novel scoring system to predict on admission the likelihood of development of delirium in ADHF patients; this system also predicts prolongation of intensive care and hospital stay.

Depressed production of beta-defensins from mouse splenic dendritic cells following thermal injury and its influence on susceptibility to infection.

PURPOSE: Beta-defensins (BDs) and dendritic cells (DC) have been described as major effectors on host antimicrobial innate immunities. In the present study, the ability of DC to produce BDs was explored using DC from normal mice and full-thickness (FT)-burned mice. METHODS: DCs were isolated from spleens of mice, and 1 × 10(6) cells/ml of them were cultured with LPS or SAC. Culture fluids harvested 24 h after cultivation were assayed for BD1 and BD3 and antibacterial activity (colony-counting, Pseudomonas aeruginosa). Also, DCs were tested for BD mRNAs by RT-PCR. RESULTS: Sixty-five percent of the bacterial killing activity was shown by the culture fluids of splenic DC from normal mice, while only 15 % killing activity was shown by the culture fluids of splenic DC from FT-burned mice. X-irradiated NOD SCID IL-2rγ(null) mice inoculated with splenic DC from FT-burned mice showed increased susceptibility to P. aeruginosa infection compared to those from normal mice. Mice splenic DC expressed BD1 mRNA constitutively and expressed BD3 mRNA after stimulation. These BDs were produced by mice splenic DC. As compared with DC from normal mice, DC from FT-burned mice produced decreased amounts of BD1 and BD3 in their culture fluids. CONCLUSIONS: These results indicate that (1) DC from spleens of mice have an ability to produce BDs, and (2) the production of BDs by DC is influenced strongly by thermally injured stress. Since FT-burned mice are susceptible to P. aeruginosa infection, BDs produced by DC may play an important role on the host's antibacterial resistance.

Thrombomodulin improved liver injury, coagulopathy, and mortality in an experimental heatstroke model in mice.

BACKGROUND: Heatstroke is a life-threatening illness and causes high mortality due to multiple organ injuries. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that plays an important role in the regulation of intravascular coagulation. In this study, we investigated the effect of TM on the inflammatory process, liver function, coagulation status, and mortality in experimental heatstroke. METHODS: Male C3H/HeN (8-10 weeks) mice were randomly assigned to the TM-treated group (TG-Pre) or nontreated heatstroke group (HS). In group TG-Pre, mice were treated with recombinant soluble TM (1 mg/kg, intraperitoneally) before heat exposure. In some experiments, recombinant soluble TM was administrated during heat exposure (TG-Delay). Heatstroke was induced by exposure to ambient temperature of 38°C for 4 hours. After heat exposure, the levels of tumor necrosis factor-α, interleukin-6, and plasma high-mobility group box 1 (HMGB1), liver function, plasma aspartate aminotransferase and alanine aminotransferase concentrations, and immunohistochemical and histopathological characteristics of the livers were determined. The coagulation status, plasma protein C levels, and thrombin-antithrombin complex levels were also measured. RESULTS: In group HS, plasma cytokines and HMGB1 concentrations increased after heat exposure. Plasma aspartate aminotransferase and alanine aminotransferase concentrations increased after heat exposure. In group HS livers, strong and extensive immunostaining for HMGB1 was observed. In addition, there was extensive hepatocellular necrosis and collapse of nuclei observed. In group HS, plasma protein C levels were suppressed and plasma thrombin-antithrombin complex levels increased. In group TG-Pre, plasma cytokines and HMGB1 concentrations were suppressed after heat exposure compared with group HS. Liver injury, coagulopathy, and mortality also improved in group TG-Pre. Furthermore, recombinant soluble TM treatment decreased mortality even with delayed treatment. CONCLUSIONS: This study demonstrated that recombinant soluble TM suppressed plasma cytokines and HMGB1 concentrations after heat exposure. Recombinant soluble TM also improved liver injury and coagulopathy. Recombinant soluble TM treatment improved mortality even with delayed treatment. Recombinant soluble TM may be a beneficial treatment for heatstroke patients.

Dexmedetomidine suppresses proinflammatory mediator production in human whole blood in vitro.

BACKGROUND: It has been demonstrated that proinflammatory mediators increase in patients with sepsis, trauma, and burns. These mediators are associated with the development of septic shock and organ dysfunction. Dexmedetomidine (DEX), a selective agonist of the α2-adrenergic receptors, is used in intensive care units for sedation. However, it still remains unclear whether DEX administration has any effects on the production of proinflammatory mediators. In this study, we investigated the effects of DEX on lipopolysaccharide (LPS)-induced production of tumor necrosis factor α, interleukin 6 (IL-6), IL-8, and high-mobility group box 1 protein in human whole blood. METHODS: Human whole blood was cultured with LPS for up to 24 hours, and LPS-induced proinflammatory mediator production was measured. Next, we tested the effect of DEX on whole blood proinflammatory mediator production. Human whole blood was cultured with LPS and various concentrations of DEX for 12 hours. Then, we investigated the influence of yohimbine, an antagonist of the α2-adrenergic receptors, on the effects of DEX. The effect of DEX on necrosis factor κB (NFκB) activation was also investigated. RESULTS: DEX suppressed tumor necrosis factor α, IL-6, IL-8, and high-mobility group box 1 protein production in human whole blood. The suppressing effects of DEX on proinflammatory mediator production were reversed by yohimbine. The results suggested that the mechanism for the suppressive effects of DEX on proinflammatory mediator production is meditated via α2-adrenergic receptors. These effects of DEX also include an inhibitory effect on NFκB activation. CONCLUSION: We demonstrate the suppressing effect of DEX on inflammatory mediator production in human whole blood after LPS stimulation. The mechanism for the suppressive effect of DEX on proinflammatory mediator production may be through the α2-adrenergic receptors and NFκB inhibition.

Lidocaine suppresses mouse Peyer's Patch T cell functions and induces bacterial translocation.

BACKGROUND: The gastrointestinal mucosa is an important route of entry for microbial pathogens. The immune cells of Peyer's patch (PP) compartments contribute to the active immune response against infection. Although local anesthetics are widely used in clinical practice, it remains unclear whether local anesthetics such as lidocaine affect PP T cell functions. METHODS: The aim of this study was to examine if lidocaine has any effects on mouse PP T cell functions. To test this, freshly isolated mouse Peyer's patch T cells were incubated with lidocaine. The effects of lidocaine on concanavalin A-stimulated PP T cell proliferation and cytokine production were assessed. The effect of lidocaine on PP T cell mitogen-activated protein kinase (MAPK) activation was also assessed. RESULTS: The results indicate that lidocaine suppresses cell proliferation, cytokine production, and MAPK activation in PP T cells. Furthermore, we found that the chronic in vivo exposure to lidocaine increases bacterial accumulation in PP. CONCLUSION: The enhanced immunosuppressive effects of lidocaine on PP T cell functions could contribute to the host's enhanced susceptibility to infection.

Photochemical synthesis of silver particles using water-in-ionic liquid microemulsions in high-pressure CO2.

Silver particles (Ag particles) were synthesized by the photoreduction of silver perchlorate (AgClO(4)) in water-in-ionic liquid (IL) microemulsions consisting of nonionic surfactant Tween 20, water, and ionic liquids, [1-butyl-3-methylimidazolium tetrafluoroborate ([BMIm][BF(4)]) or 1-octyl-3-methylimidazolium tetrafluoroborate ([OMIm][BF(4)])], mixed with a high-pressure (25 MPa) CO(2). The time evolution of the Ag particle formation by photoreduction was investigated by UV-Vis, cryo-TEM, extended X-ray absorption fine structure (EXAFS), and small-angle X-ray scattering (SAXS) measurements. In the particle formation process, aggregation and precipitation of Ag particles were suppressed under high-pressure CO(2). The average diameters of the metallic Ag particles prepared in water-in-[BMIm][BF(4)] and water-in-[OMIm][BF(4)] microemulsions were estimated from TEM to be 3.2 and 3.7 nm, respectively. SAXS analysis shows that the average diameters of the water droplets, which consisted of ionic precursors of AgClO(4) and Ag particles (or Ag aggregates), were estimated to be about 30-40 nm. In the process of Ag particle formation, the water droplet size under high-pressure CO(2) is more effectively regulated than that under ambient air, thereby preventing Ag particles from aggregating and precipitating.

Lidocaine enhances apoptosis and suppresses mitochondrial functions of human neutrophil in vitro.

BACKGROUND: Neutrophils play an essential role in innate immunity and against infection. Mitochondria are organelles that produce energy in the form of adenosine triphosphate (ATP), which is required for maintaining the function and structure of cells and organs. Although local anesthetics (LAs) are widely used in clinical practice, it remains unclear whether LAs such as lidocaine, ropivacaine, and bupivacaine affect neutrophil mitochondrial functions. The aim of this study was to examine whether LAs have any effects on human neutrophil mitochondrial functions. METHODS: Freshly isolated human neutrophils were incubated with lidocaine, ropivacaine, or bupivacaine. The oxidative burst and phagocytic activity of neutrophils and apoptotic rate of neutrophils were measured to assess the effect of LAs on neutrophil functions. The ATP concentration, mitochondrial transmembrane potential (Deltapsim), and neutrophil mitochondrial morphology were also measured to evaluate the effect of LAs on mitochondrial functions. RESULTS: Lidocaine (400 microm) induced a reduction in the oxidative burst and phagocytosis activity of neutrophils by approximately 20%. The ATP concentration was significantly lower in lidocain-treated neutrophils compared with control neutrophils (876 +/- 25 vs. 1,332 +/- 76 pmol/10(6) neutrophils; p < 0.05). Mitochondrial transmembrane potential (Deltapsim) was also significantly lower in lidocaine-treated neutrophils compared with control neutrophils (p < 0.05). Lidocaine also induced mitochondrial structural changes and induced apoptosis of neutrophils. Ropivacaine and bupivacaine had no effect on neutrophil functions including mitochondrial function. Furthermore, the study of mitochondrial function depletion demonstrated that neutrophil function requires active mitochondrial function. CONCLUSIONS: Although ropivacaine and bupivacaine had no effect on neutrophil and mitochondrial functions, lidocaine suppressed neutrophil function, inhibited ATP synthesis, reduced mitochondrial membrane potential, and induced apoptosis.

A platelet activating factor receptor antagonist inhibits cytokine production in human whole blood by bacterial toxins and live bacteria.

UNLABELLED: We previously reported that a platelet-activating factor receptor (PAFR) antagonist (TCV-309) suppressed lipopolysaccharide (LPS)-induced mortality and tumor necrosis factor (TNF) production in mice. However, the effect of TCV-309 on cytokine production induced by Staphylococcus enterotoxin B (SEB) or live bacteria has not been reported. In this study we investigated the effect of TCV-309 on cytokine production in human whole blood induced by LPS, SEB, and both Gram-positive and -negative bacteria. Human whole blood diluted 5:1 (980 microL) was placed in the wells of a 24-well plate. Ten microliters of LPS, SEB, Escherichia coli O18 K(+), or Staphylococcus aureus were added to each well. After incubation at 37 degrees C for 6 h, TNF, interleukin (IL)-6, and IL-8 in the culture medium were measured. TCV-309 did not affect the growth of either E. coli or S. aureus bacteria in the culture medium for the 6 h incubation. LPS, SEB, and both E. coli and S. aureus induced TNF, IL-6, and IL-8 in human whole blood. TCV-309 significantly inhibited the production of TNF, IL-6, and IL-8 induced by LPS, SEB, and bacteria. A PAFR antagonist suppressed cytokine production induced by LPS, SEB, and both Gram-positive and -negative bacteria in human whole blood. A PAFR plays an important role of producing proinflammatory cytokines induced by both toxins and live bacteria. IMPLICATIONS: The platelet-activating factor receptor plays an important role in producing proinflammatory cytokines induced by bacterial toxins, such as lipopolysaccharide,Staphylococcus enterotoxin B, and live Gram-positive and Gram-negative bacteria.

The effect of local anesthetics on monocyte mCD14 and human leukocyte antigen-DR expression.

UNLABELLED: It has been demonstrated that local anesthetics have several effects on the immune system. Monocytes and macrophages are essential components of the host response to microbial infection; however, the effect of local anesthetics on monocyte surface receptor expression remains unclear. We designed this study to investigate the effects of local anesthetics on monocyte mCD14 and human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced or staphylococcal enterotoxin B (SEB)-induced tumor necrosis factor (TNF)-alpha production. Blood samples were obtained from 10 healthy volunteers. The effects of local anesthetics on LPS- or SEB-induced TNF-alpha production were determined by using an enzyme-linked immunosorbent assay. After different doses of local anesthetics were added, the blood was stimulated with LPS (10 ng/mL) or SEB (10 micro g/mL) for 4 h. The effects of local anesthetics on monocyte mCD14 and HLA-DR expression were measured by dual monoclonal antibody staining and flow cytometry. Local anesthetics showed no effect on LPS- or SEB-induced TNF-alpha production in human whole blood. Local anesthetics suppressed monocyte HLA-DR expression in a dose-dependent manner (P < 0.05) but had no effect on monocyte mCD14 expression. This study demonstrated that local anesthetics suppress HLA-DR expression on the surface of human monocytes. IMPLICATIONS: Monocyte surface receptors have a crucial role in the host response to microbial infection. We investigated the effects of local anesthetics on monocyte mCD14 and human leukocyte antigen (HLA)-DR expression. Our results show that local anesthetics suppress HLA-DR expression on the surface of human monocytes.

Th1, Th2, and activated T-cell marker and clinical prognosis in peripheral T-cell lymphoma, unspecified: comparison with AILD, ALCL, lymphoblastic lymphoma, and ATLL.

A new World Health Organization classification was recently proposed. However, classification of peripheral T-cell lymphomas remains to be clarified. Particularly, unspecified type was considered as a heterogeneous category. Here we studied the expressions of chemokine receptors, Th1-associated CXCR3 and CCR5 and Th2-associated marker ST2(L), and activated T-cell receptor OX40/CD134 in 185 patients with nodal T-cell lymphoma, and evaluated the relationship to prognosis. Their expression patterns correlated with the specific subtype of nodal T-cell lymphoma, such as angioimmunoblastic T-cell lymphoma (AILD), anaplastic large cell lymphoma (ALCL), and in peripheral T-cell lymphoma (PTCL), unspecified. In AILD, almost all cases were immunoreactive for OX40/CD134 (96%) and for CXCR3 (89%). In ALCL, all cases were immunonegative for OX40/CD134, and only a few cases (24%) were immunoreactive for CXCR3, whereas almost all cases (94%) were positive for ST2(L). Cases of PTCL, unspecified, were divided into 2 groups; group 1 (cases positive for either ST2(L), CCR5, or CXCR3) tended to show favorable prognosis compared with group 2 (cases negative for ST2(L), CCR5, and CXCR3). Our results indicate that further subtyping of PTCL, unspecified, into groups 1 and 2 could be significant for evaluating prognosis and understanding the functional role of these tumors.

Follicular lymphoma of the stomach: immunohistochemical and molecular genetic studies.

The gastrointestinal (GI) tract is the most common site for the development of extranodal non-Hodgkin's lymphomas, with most cases having a diffuse architectural pattern. Follicular lymphoma (FL) of the stomach is a very rare disease, and little is known about the immuno-histochemical and molecular genetic characteristics of this type of lymphoma. Despite their rarity, FLs are an important consideration in the differential diagnosis of follicular hyperplasia of mucosa-associated lymphoid tissue (MALT), a relatively frequently encountered lesion with the potential to cause significant diagnostic difficulty, especially when assessment is based on scanty biopsy material. We report a 57-year-old woman with gastric FL, and describe the results of immunohistochemical and molecular genetic studies.

Chromosomal and comparative genomic analyses of HHV-8-negative primary effusion lymphoma in five HIV-negative Japanese patients.

A rare subset of HIV lymphoma, known as primary effusion lymphoma (PEL), is a high-grade tumour carrying human herpes virus 8 (HHV-8). Very little is known about genomic aberration in PEL, and only a few HIV-negative PEL have been reported. Here we report the results of chromosomal analysis and comparative genomic hybridisation (CGH) conducted to detect regions of gain and loss, in five HIV-negative Japanese cases of HHV-8-negative PEL. All patients except one (35-year-old female) were elderly men and the morphologic examination showed large cell type. PEL expressed B-cell-associated and activation-associated antigens, and exhibited clonal immunoglobulin genes. No HHV-8 was detected in all four examined cases, but Epstein-Barr virus (EBV) was detected in one case. Genomic abnormalities and aberrations were identified in all HHV-8/HIV-negative PEL. CGH studies showed gain in 19 of 24 chromosomes. Gains of 3q13-27, 8q24, 10q21-23 and Yq were detected in two of the five cases, but other gains were noted in each case. Chromosomal analysis revealed complex abnormalities both in numbers and structures. Burkitt lymphoma-associated t(8;22) was detected in one case, but +8 chromosome and c-myc amplification were detected in the other three cases by Southern blot and/or fluorecence in situ hybridization (FISH). Abnormality of chromosome 8, which associates with c-myc, was detected in four of the five HHV-8/HIV-negative PEL. However, the other common genomic abnormalities of HHV-8/HIV-negative PEL were not detected in our study, but the complex abnormalities seemed to be true rather than the usual large B-cell lymphoma. Our results suggest that multi-step genomic abnormalities might be associated in HHV-8/HIV-negative PEL tumorigenesis.

Infiltration of Th1 and Th2 lymphocytes around Hodgkin and Reed-Sternberg (H&RS) cells in Hodgkin disease: Relation with expression of CXC and CC chemokines on H&RS cells.

Hodgkin disease (HD) is characterized by the presence of Hodgkin and Reed-Sternberg cells (H&RS) and a prominent lymphocytic infiltration. Various CXC and CC chemokines [e.g., interferon-gamma-inducible protein-10 (IP10), monokine induced by interferon-gamma (MIG) and TARC] are expressed on H&RS cells. Our study was designed to investigate the expression of MIG, IP10 and TARC on H&RS cells and their relations on lymphocyte infiltration. Immunohistochemical staining was performed using antibodies for CXCR3 (a specific receptor for IP10 and MIG), which is characteristic of Th1 helper phenotype and CCR3, CCR4 and ST2, which are features of Th2 cells. We studied 15 cases of HD [lymphocyte predominance (LP) type, 2; mixed cellularity (MC) type, 6; and nodular sclerosis (NS) type, 7]. All 6 MC cases contained TARC-, IP10- and MIG-expressing H&RS cells, however only 2 of 5 NS cases contained TARC-expressing H&RS cells, 3 of 7 NS contained MIG-expressing H&RS cells and only 1 of 7 NS contained IP10-expressing H&RS cells. Neither of the 2 LP cases contained HR&S cells that expressed these chemokines. The chemokines were more frequently expressed by MC than by NS and LP types. IP10-, MIG- and TARC-positive HD cases contained higher numbers of Th2 lymphocytes (ST2- CCR3- or CCR4-positive lymphocytes), compared to IP10-, MIG- and TARC-negative HD cases (p < 0.05 or <0.5). The number of CXCR3 (MIG and IP10 receptor)-positive lymphocytes (Th1 lymphocytes) was not different between MIG- and IP10-positive and -negative HD. Lymphocytes surrounding MIG- and IP10-positive H&RS cells were more frequently CXCR3-positive, however, compared to MIG- and IP10-negative cases. The CCR4 (TARC receptor)-positive lymphocytes, surrounding H&RS cells, were minority and the surrounding lymphocytes were not different between TARC-positive and negative cases. Our results indicate that MIG, IP10 and TARC chemokines influenced the response of Th2 cells in HD. It is possible, however, that IP10 and MIG may locally influence Th1 cells via cell migration.

Clinicopathological features of gastric B-cell lymphoma: a series of 317 cases.

The stomach is a common site of extranodal malignant lymphoma. Here we examined the clinicopathological features of 317 gastric B-cell lymphomas and characterized the differences among low-grade mucosa-associated lymphoid tissue (MALT) lymphomas (LG), high-grade MALT lymphomas (HG), follicular lymphomas (FL) and diffuse large B-cell lymphomas (DL). Cases included 126 DL, 71 HG, 98 LG, 10 FL, three Burkitt's lymphoma and nine of undefined type. The age range of patients was as follows: LG, 14-96 years (mean, 61.1); HG, 20-87 years (mean, 63.9); DL, 16-88 years (mean, 62.8); and FL, 54-76 years (mean, 65.5). There were no differences in age with respect to tumor type. There were more women patients with LG (female:male, 55:43), while males predominated among DL patients (54:72). The sexes were represented almost equally in HG cases (34:37). Histological findings, especially in DL tumors, correlated significantly to the gross appearance of mass formation. Dutcher bodies were encountered mainly in HG or LG cases. Our results showed no differences in age, sex or site of disease between LG, HG and DL tumors. However, the grade of malignancy correlated strongly to gross appearance. Dutcher bodies were important for the diagnosis of gastric MALT lymphoma.