Resistin Is a Novel Marker for Postoperative Pain Intensity.

BACKGROUND: Pro- and anti-inflammatory cytokines (adipokines) associated with adipose tissue can modulate inflammatory processes and lead to systemic inflammatory conditions such as metabolic syndrome. In the present pilot study, we investigated 3 major adipokines (leptin, adiponectin, and resistin) and 2 nonspecific proinflammatory cytokines (tumor necrosis factor α and interleukin-6) with regard to their association with postoperative pain intensity. METHODS: We analyzed a total of 45 single-nucleotide polymorphisms of the adipokines in 57 patients with postlaparotomy pain. We adjusted for multiple testing to reduce the chance of false-positive results by controlling the false discovery rate. Serum levels of the adipokines and proinflammatory cytokines were measured in another 36 patients undergoing laparotomy. A stepwise multiple linear regression analysis using these measurements and opioid dosages as independent variables was performed to explore the factors associated with postoperative pain. RESULTS: Only 1 variant of the resistin gene (rs3745367) demonstrated a significant association with postoperative pain (P < .002). Patients exhibiting homozygosity for the minor alleles (n = 7; numerical rating scale [NRS], 2.3 ± 1.3) demonstrated lower pain intensity compared with those exhibiting homozygosity for the major alleles (n = 29; NRS, 3.8 ± 1.0; P = .004) and heterozygosity for the minor alleles (n = 21; NRS, 4.2 ± 0.8; P < .001). Only serum resistin levels showed a positive association with postoperative pain. CONCLUSIONS: A genetic variant of resistin and serum resistin levels were associated with postoperative pain intensity, while other adipokines and cytokines exhibit no such association. Resistin can alter the inflammatory responses in postoperative wounds, although it could be a determinant factor that is independent of inflammatory processes. Resistin may be a novel marker for postoperative pain intensity.

IFN-ß Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute Respiratory Distress Syndrome-related Mortality.

IFN-ß is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-ß for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-ß 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-α and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-α or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-ß reversed the TNF-α/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis → pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-ß improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.

Early-phase Innate Immune Suppression in Murine Severe Sepsis Is Restored with Systemic Interferon-ß.

BACKGROUND: Sepsis is a leading cause of death in the intensive care unit. Immune modulatory therapy targeting sepsis-associated proinflammatory responses has not shown survival benefit. Here, the authors evaluated innate immunity at the early stage of murine mild or severe peritoneal sepsis induced by cecal ligation and puncture, and the effect of systemic interferon-ß, a potent inflammatory mediator, on severe sepsis as well as its mechanism of action. METHODS: Mild and severe sepsis was induced in C57BL/6 mice by cecal ligation and puncture with 22- and 18-gauge needles for puncture, respectively. Interferon-ß (700 U/g) was subcutaneously administered either before or 12 h after cecal ligation and puncture for the severe sepsis group. RESULTS: Severe sepsis resulted in significantly lower 6-day survival rates than mild sepsis (n = 48, 25% vs. n = 11, 81.8%, P = 0.002), significantly less phagocytic capacity of peritoneal exudate cells, and lower CXC chemokine receptor-2 expression on circulating neutrophils at 24 h after cecal ligation and puncture. Interferon-ß administration 12 h after cecal ligation and puncture associated with significantly improved survival (n = 34, 52.9%, P = 0.017) increased the number and function of peritoneal exudate cells, peritoneal/systemic inflammatory cytokine/chemokine concentrations, and CXC chemokine receptor-2 on neutrophils, compared with the severe sepsis controls. However, those responses were not observed in the prophylactic interferon-ß group (n = 24). Interferon-ß increased lipopolysaccharide-induced interleukin-6 messenger RNA/protein expression of lipopolysaccharide-tolerant murine peritoneal macrophages, which was not observed in nontolerant cells. CONCLUSIONS: In severe sepsis, immune suppression occurs within 24 h and is associated with worse mortality. Interferon-ß given after the onset of peritonitis restores impaired innate immunity in vivo and in vitro.

Prevalence of malignant hyperthermia and relationship with anesthetics in Japan: data from the diagnosis procedure combination database.

BACKGROUND: Malignant hyperthermia (MH) is a rare but life-threatening disease that occurs during general anesthesia. The actual prevalence of MH remains unclear, and the association between MH and various anesthetic drugs remains controversial because of a lack of universal reporting. METHODS: Using the Japanese Diagnosis Procedure Combination database, we collected data of inpatients who had general anesthesia between July and December 2006-2008. Patients' age, gender, diagnoses, procedures, and the use of drugs during anesthesia, including volatile agents, muscle relaxants, and propofol, were investigated. Univariate comparisons were made to examine the relationship of each anesthetic drug or demographic factor with the occurrence of MH. RESULTS: Of 1,238,171 surgical patients undergoing general anesthesia, we identified 17 MH patients. Only one in-hospital death was identified. Men were significantly more likely to contract MH(odds ratio: 3.49; 95% CI 1.14 -10.7; P=0.029). No MH patient was found among 19,871 suxamethonium users. The prevalence of MH was relatively high in users of sevoflurane and rocuronium compared with nonusers but was not statistically significant [corrected].. CONCLUSIONS: No single drug was significantly associated with the occurrence of MH. Data should be continuously compiled, and further analyses with larger numbers of cases are necessary to identify possible causative agents.

A standardized blood test for the routine clinical diagnosis of impaired GM-CSF signaling using flow cytometry.

Impaired signaling by granulocyte/macrophage-colony stimulating factor (GM-CSF) drives the pathogenesis of two diseases (autoimmune and hereditary pulmonary alveolar proteinosis (PAP)) representing over ninety percent of patients who develop PAP syndrome but not a broad spectrum of diseases that cause PAP by other mechanisms. We previously exploited the ability of GM-CSF to rapidly increase cell-surface CD11b levels on neutrophils (CD11bSurface) to establish the CD11b stimulation index (CD11b-SI), a test enabling the clinical research diagnosis of impaired GM-CSF signaling based on measuring CD11bSurface by flow cytometry using fresh, heparinized blood. (CD11b-SI is defined as GM-CSF-stimulated- CD11bSurface minus unstimulated CD11bSurface divided by un-stimulated CD11bSurface multiplied by 100.) Notwithstanding important and unique diagnostic utility, the test is sensitive to experimental conditions that can affect test performance. The present study was undertaken to optimize and standardize CD11b-SI test for detecting impaired GM-CSF signaling in heparinized human blood specimens from PAP patients. Results demonstrated the test was sensitive to choice of anticoagulant, pretesting incubation on ice, a delay between phlebotomy and test performance of more than one hour, and the concentration GM-CSF used to stimulate blood. The standardized CD11b-SI test reliably distinguished blood specimens from autoimmune PAP patients with impaired GM-CSF signaling from those of health people with normal signaling. Intra-subject differences were smaller than inter-subject differences in repeated measures. Receiver operating characteristic curve analysis identified a CD11b-SI test result of 112 as the optimal cut off threshold for diagnosis of impaired GM-CSF signaling in autoimmune PAP for which the sensitivity and specificity were both 100%. These results support the use of this standardized CD11b-SI for routine clinical identification of impaired GM-CSF signaling in patients with autoimmune PAP. The CD11b-SI may also have utility in clinical trials of novel therapeutic strategies targeting reduction in GM-CSF bioactivity now under evaluation for multiple common autoimmune and inflammatory disorders.