The critical role of pancreatic stone protein/regenerating protein in sepsis-related multiorgan failure.

Introduction: Multiple organ dysfunction syndrome (MODS) is common in patients with sepsistic admitted to an intensive care unit (ICU) and greatly increases mortality. Pancreatic stone protein/regenerating protein (PSP/Reg) is a type of C-type lectin protein that is overexpressed during sepsis. This study aimed to evaluate the potential involvement of PSP/Reg in MODS development in patients with sepsis. Materials and methods: The relationship between circulating PSP/Reg levels, patient prognosis, and progression to MODS was analyzed in patients with sepsis admitted to the ICU of a general tertiary hospital. Furthermore, to examine the potential involvement of PSP/Reg in sepsis-induced MODS, a septic mouse model was established per the cecal ligation and puncture procedure, randomized into three groups, and subjected to a caudal vein injection of recombinant PSP/Reg at two different doses and phosphate-buffered saline. Survival analyses and disease severity scoring were performed to evaluate the survival status of the mice; enzyme-linked immunosorbent assays were performed to detect the levels of inflammatory factors and organ-damage markers in murine peripheral blood; terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed to measure apoptosis levels in lung, heart, liver, and kidney tissue sections and to visualize the degree of organ damage in the mouse model; myeloperoxidase activity assay, immunofluorescence staining, and flow cytometry were performed to detect neutrophil infiltration levels in vital murine organs and the activation indexes of neutrophils. Results and discussion: Our findings indicated that Circulating PSP/Reg levels were correlated with patient prognosis and sequential organ failure assessment scores. Furthermore, PSP/Reg administration increased disease severity scores, shortened survival time, increased the TUNEL-positive staining rate, and increased the levels of inflammatory factors, organ-damage markers, and neutrophil infiltration in the organs. Neutrophils can be activated by PSP/Reg to an inflammatory state, both in vivo and in vitro, which is characterized by the increased levels of intercellular adhesion molecule 1 and CD29. Conclusion: Patient prognosis and progression to MODS can be visualized by monitoring PSP/Reg levels upon ICU admission. Additionally, PSP/Reg administration in animal models exacerbates the inflammatory response and severity of multiorgan damage, which may be accomplished by promoting the inflammatory state of neutrophils.

Reprogramming of histone methylation controls the differentiation of monocytes into macrophages.

Subset heterogeneity of the mononuclear phagocyte system (MPS) is controlled by defined transcriptional networks and programs; however, the dynamic establishment of programs that control broad, orchestrated expression of transcription factors (TFs) during the progression of monocyte-into-phagocyte (MP) differentiation remains largely unexplored. By using chromatin immunoprecipitation assays, we show the extensive trimethylation of histone H3 lysine 4 (H3K4me3) as well as histone H3 lysine 27 (H3K27me3) occupancy with broad footprints at the promoters of MP differentiation-related TFs, such as HOXA and FOXO genes, KLF4, IRF8 and others. The rapid repression of HOXA genes was closely associated with the MP differentiation program. H3K4me3 participates in regulating HOXA genes at mild and terminal differentiation periods, while H3K27me3 maintains low-level expression of HOXA genes at phagocytic maintenance periods. Furthermore, the reprogramming of H3K27me3 plays a major role in the up-regulation of KLF4 and FOXO genes during MP differentiation. Importantly, the pharmacological inhibition of H3K4me3 and/or H3K27me3 strikingly promotes the differentiation programs of THP-1 and K562 cells. Together, these findings elucidate mechanisms crucial to the dynamic establishment of epigenetic memory, which is central to the maintenance of the MP differentiation blockade.

Effect of early goal directed therapy on tissue perfusion in patients with septic shock.

BACKGROUND: This study aimed to observe the effect of early goal directed therapy (EGDT) on tissue perfusion, microcirculation and tissue oxygenation in patients with septic shock. METHODS: Patients with early septic shock (<24 hours) who had been admitted to the ICU of Zhongda Hospital Affiliated to Southeast University from September 2009 through May 2011 were enrolled (research time: 12 months), and they didn't meet the criteria of EGDT. Patients who had one of the following were excluded: stroke, brain injury, other types of shock, severe heart failure, acute myocardial infarction, age below 18 years, pregnancy, end-stage disease, cardiac arrest, extensive burns, oral bleeding, difficulty in opening the mouth, and the onset of septic shock beyond 24 hours. Patients treated with the standard protocol of EGDT were included. Transcutaneous pressure of oxygen and carbon dioxide (PtcO2, PtcCO2) were monitored and hemodynamic measurements were obtained. Side-stream dark field (SDF) imaging device was applied to obtain sublingual microcirculation. Hemodynamics, tissue oxygen, and sublingual microcirculation were compared before and after EGDT. If the variable meets the normal distribution, Student's t test was applied. Otherwise, Wilcoxon's rank-sum test was used. Correlation between variables was analyzed with Pearson's product-moment correlation coefficient method. RESULTS: Twenty patients were involved, but one patient wasn't analyzed because he didn't meet the EGDT criteria. PtcO2 and PtcCO2 were monitored in 19 patients, of whom sublingual microcirculation was obtained. After EGDT, PtcO2 increased from 62.7±24.0 mmHg to 78.0±30.9 mmHg (P<0.05) and tissue oxygenation index (PtcO2/FiO2) was 110.7±60.4 mmHg before EGDT and 141.6±78.2 mmHg after EGDT (P<0.05). The difference between PtcCO2 and PCO2 decreased significantly after EGDT (P<0.05). The density of perfused small vessels (PPV) and microcirculatory flow index of small vessels (MFI) tended to increase, but there were no significant differences between them (P>0.05). PtcO2, PtcO2/FiO2, and PtcCO2 were not linearly related to central venous saturation, lactate, oxygen delivery, and oxygen consumption (P>0.05). CONCLUSION: Peripheral perfusion was improved after EGDT in patients with septic shock, and it was not exactly reflected by the index of systemic perfusion.

[Passive leg raising predicts volume responsiveness in patients with septic shock].

OBJECTIVE: To evaluate the hemodynamic response to passive leg raising (PLR) indicates fluid responsiveness in patients with septic shock. METHODS: Twenty patients with septic shock, considered for fluid challenge (FC), were enrolled in the study from June 2009 to May 2010. Hemodynamic changes were determined by pulse-contour derived cardiac index at baseline, before and after PLR, return to baseline for 10 min, before and after fluid challenge (250 ml saline for 10 min). An increase of SV after fluid challenge (FC-ΔSV) ≥ 10% were defined responders. RESULTS: Twenty patients with septic shock were included in the study. PLR and fluid challenge were performed 46 instances, among which 15 instances were defined as response group. SV and pulse pressure induced by PLR (PLR-ΔSV and PLR-ΔPP) were increased significantly in response group [(76 ± 19) ml vs. (65 ± 18) ml, (73 ± 20) mmHg vs. (62 ± 20) mmHg (1 mmHg = 0.133 kPa), P < 0.05], while in nonresponse group there were no significant change. PLR-ΔSV and PLR-ΔPP were correlated with FC-ΔSV (r = 0.51, P = 0.001; r = 0.45, P = 0.006), central venous pressure (CVP) were unrelated with FC-ΔSV. Area under curve (AUC) for PLR-ΔSV, PLR-ΔPP and stroke volume variation (SVV) were 0.846, 0.791 and 0.708. PLR-ΔSV ≥ 12.5% predicted fluid responsiveness with sensitivity of 80% and specificity of 93.5%. PLR-ΔPP ≥ 9.5% predicted fluid responsiveness with sensitivity of 73.3% and specificity of 83.9%. CONCLUSIONS: PLR-ΔSV and PLR-ΔPP can predict fluid responsiveness in patients with septic shock. PLR-ΔSV and PLR-ΔPP have a greater ability in predicting volume responsiveness than CVP and SVV.

[Timing of tracheotomy on the prognosis of patients with prolonged mechanical ventilation: a meta-analysis of randomized controlled trials].

OBJECTIVE: To evaluate the effect of timing of tracheotomy on the prognosis of prolonged mechanically ventilated patients. METHODS: Randomized controlled trials (RCTs) that studied the effect of timing of tracheotomy on the prognosis of prolonged mechanically ventilated patients were searched from Pubmed, Embase, The Cochrane Library, CBM during January 1990 to June 2010. The quality of the RCTs was evaluated. Meta-analysis of timing of tracheotomy on the prognosis of prolonged mechanically ventilated patients were conducted using the methods recommended by the Cochrane Collaboration. Definition of early tracheotomy was the patients performed tracheotomy during 10 days after admission to hospital or ICU, mechanical ventilation or intubation. Late tracheotomy was defined tracheotomy performed beyond 10 days of admission to hospital or ICU, mechanical ventilation or intubation; or those mechanically ventilated through intubation all the time. RESULTS: Eight hundred and twenty eight patients, 411 in early tracheotomy group and 417 in late tracheotomy group, from 6 RCTs were included in the analysis of data. The meta-analysis showed that early tracheotomy could reduce mortality of patients (RR: 0.81, 95%CI: 0.66 - 0.99, P = 0.04); but it didn't significantly alter the incidence of pneumonia (RR:0.89, 95%CI: 0.68 - 1.17, P = 0.41), mechanical ventilation days (mean difference: -2.19, 95%CI: -9.86 - 5.49, P = 0.58) and length of ICU stay (mean difference: -5.65, 95%CI: -17.11 - 5.81, P = 0.33). CONCLUSIONS: In critically ill adult patients who require prolonged mechanical ventilation, early tracheotomy performed at an earlier stage reduces the mortality, but doesn't reduce the incidence of pneumonia and shorten the mechanical ventilation days and ICU length of stay. But more high quality RCTs are required to confirm it.