Turning cationic antimicrobial peptide KR-12 into self-assembled nanobiotics with potent bacterial killing and LPS neutralizing activities.

Gram-negative sepsis has become a substantial and escalating global healthcare challenge due to the growing antibiotic resistance crisis and the sluggish development of new antibiotics. LL-37, a unique Cathelicidin species found in humans, exhibits a wide range of bioactive properties, including direct bactericidal effects, inflammation regulation, and LPS neutralization. KR-12, the smallest yet potent peptide fragment of LL-37, has been modified to create more effective antimicrobials. In this study, we designed two myristoylated derivatives of KR-12, referred to as Myr-KR-12N and Myr-KR-12C. These derivatives displayed remarkable ability to spontaneously assemble into nanoparticles when mixed with deionized water. Myristoylated KR-12 derivatives exhibited broad-spectrum and intensified bactericidal activity by disrupting bacterial cell membranes. In particular, Myr-KR-12N showed superior capability to rescue mice from lethal E. coli-induced sepsis in comparison with the conventional antibiotic meropenem. We also confirmed that the myristoylated KR-12 nanobiotic possesses significant LPS binding capacity and effectively reduces inflammation in vitro. In an in vivo context, Myr-KR-12N outperformed polymyxin B in rescuing mice from LPS-induced sepsis. Crucially, toxicological assessments revealed that neither Myr-KR-12N nor Myr-KR-12C nanobiotics induced meaningful hemolysis or caused damage to the liver and kidneys. Collectively, our study has yielded an innovative nanobiotic with dual capabilities of bactericidal action and LPS-neutralization, offering substantial promise for advancing the clinical translation of antimicrobial peptides and the development of novel antibiotics. This addresses the critical need for effective solutions to combat Gram-negative sepsis, a pressing global medical challenge.

Analysis and validation of diagnostic biomarkers and immune cell infiltration characteristics in pediatric sepsis by integrating bioinformatics and machine learning.

BACKGROUND: Pediatric sepsis is a complicated condition characterized by life-threatening organ failure resulting from a dysregulated host response to infection in children. It is associated with high rates of morbidity and mortality, and rapid detection and administration of antimicrobials have been emphasized. The objective of this study was to evaluate the diagnostic biomarkers of pediatric sepsis and the function of immune cell infiltration in the development of this illness. METHODS: Three gene expression datasets were available from the Gene Expression Omnibus collection. First, the differentially expressed genes (DEGs) were found with the use of the R program, and then gene set enrichment analysis was carried out. Subsequently, the DEGs were combined with the major module genes chosen using the weighted gene co-expression network. The hub genes were identified by the use of three machine-learning algorithms: random forest, support vector machine-recursive feature elimination, and least absolute shrinkage and selection operator. The receiver operating characteristic curve and nomogram model were used to verify the discrimination and efficacy of the hub genes. In addition, the inflammatory and immune status of pediatric sepsis was assessed using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). The relationship between the diagnostic markers and infiltrating immune cells was further studied. RESULTS: Overall, after overlapping key module genes and DEGs, we detected 402 overlapping genes. As pediatric sepsis diagnostic indicators, CYSTM1 (AUC = 0.988), MMP8 (AUC = 0.973), and CD177 (AUC = 0.986) were investigated and demonstrated statistically significant differences (P < 0.05) and diagnostic efficacy in the validation set. As indicated by the immune cell infiltration analysis, multiple immune cells may be involved in the development of pediatric sepsis. Additionally, all diagnostic characteristics may correlate with immune cells to varying degrees. CONCLUSIONS: The candidate hub genes (CD177, CYSTM1, and MMP8) were identified, and the nomogram was constructed for pediatric sepsis diagnosis. Our study could provide potential peripheral blood diagnostic candidate genes for pediatric sepsis patients.

Prediction of postoperative infection in elderly using deep learning-based analysis: an observational cohort study.

Elderly patients are susceptible to postoperative infections with increased mortality. Analyzing with a deep learning model, the perioperative factors that could predict and/or contribute to postoperative infections may improve the outcome in elderly. This was an observational cohort study with 2014 elderly patients who had elective surgery from 28 hospitals in China from April to June 2014. We aimed to develop and validate deep learning-based predictive models for postoperative infections in the elderly. 1510 patients were randomly assigned to be training dataset for establishing deep learning-based models, and 504 patients were used to validate the effectiveness of these models. The conventional model predicted postoperative infections was 0.728 (95% CI 0.688-0.768) with the sensitivity of 66.2% (95% CI 58.2-73.6) and specificity of 66.8% (95% CI 64.6-68.9). The deep learning model including risk factors relevant to baseline clinical characteristics predicted postoperative infections was 0.641 (95% CI 0.545-0.737), and sensitivity and specificity were 34.2% (95% CI 19.6-51.4) and 88.8% (95% CI 85.6-91.6), respectively. Including risk factors relevant to baseline variables and surgery, the deep learning model predicted postoperative infections was 0.763 (95% CI 0.681-0.844) with the sensitivity of 63.2% (95% CI 46-78.2) and specificity of 80.5% (95% CI 76.6-84). Our feasibility study indicated that a deep learning model including risk factors for the prediction of postoperative infections can be achieved in elderly. Further study is needed to assess whether this model can be used to guide clinical practice to improve surgical outcomes in elderly.

Triggering receptor expressed on myeloid Cells-2 (TREM2) inhibits steroidogenesis in adrenocortical cell by macrophage-derived exosomes in lipopolysaccharide-induced septic shock.

PURPOSE: Endogenously produced glucocorticoids exhibit immunomodulating properties and are of pivotal importance for sepsis outcome. Uncontrolled activation of the immune-adrenal crosstalk increases the risk of sepsis-related death. Triggering receptor expressed on myeloid cells-2 (TREM2) is richly expressed on macrophages and has been demonstrated to improve outcome of sepsis by enhancing elimination of pathogens. However, the role and mode of action of macrophage TREM2 on adrenocortical steroidogenesis remains unclear in septic shock. METHODS: The acute septic shock model was established by intraperitoneally challenging wild-type (WT) and TREM2 knock-out (Trem2-/-) mice with lipopolysaccharide (LPS, 30 mg/kg). The mice were assessed for TREM2 expression and local inflammation in adrenal gland and for synthesis of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in vivo. Bone marrow-derived macrophages or macrophage-derived exosomes were isolated from WT and Trem2-/- mice and were co-cultured with adrenocortical cells. The expression of steroidogenic enzymes and corticosterone production was assessed. RESULTS: Genetic deficiency of TREM2 caused significantly higher corticosterone levels at the early stage of LPS-induced septic shock; whereas TREM2 deficiency neither increased CRH and ACTH nor exacerbated the inflammation in adrenocortical tissue during septic shock. Ex vivo study revealed that Trem2-/- macrophages significantly promoted the expression of steroidogenic enzymes and increased production of corticosterone. Furthermore, Trem2-/- macrophage-derived exosomes were able to mimic Trem2-/- macrophages in enhancing adrenocortical steroidogenesis. CONCLUSIONS: At the early stage of LPS-induced septic shock, corticosterone biosynthesis can be inhibited by macrophage TREM2 in adrenocortical cells, which might partially associate with macrophage-derived exosomes.

Postoperative infectious complications in elderly patients after elective surgery in China: results of a 7-day cohort study from the International Surgical Outcomes Study.

AIM: Despite initiatives to increase elderly patients' access to surgical treatments, the prevalence and impact of postoperative infectious complications (PICs) in elderly patients in China are poorly described. The aim of our study was to describe PICs and associated mortality in elderly patients undertaking elective surgery in China. METHODS: We analyzed data about elderly patients from China during the International Surgical Outcomes Study (ISOS), a 7-day prospective cohort study of outcomes after elective surgery in in-patient adults. All elderly patients (age ≥60 years) from 28 hospitals in China included in the ISOS study were included in this study as well. A review of 2014 elderly patients who underwent elective surgery in April 2014 was conducted. RESULTS: Of 2014 elderly patients, 209 (10.4%) developed at least one postoperative complication. Infectious complications were most frequent, affecting 154 patients (7.6%); there was one death, or 0.6% 30-day mortality, which was a significantly higher rate than among patients without PICs (0%). The most frequent infectious complication was superficial surgical-site infection (3.3%). The length of hospital stay was longer in elderly patients with PICs than in those without PICs. Moreover, a total of 142 elderly patients (7.1%) were routinely sent to critical care after surgery, of whom 97 (68.3%) developed PICs. Compared to elderly patients admitted to a standard ward, those admitted to critical care immediately after surgery had a higher postoperative complication rate and critical care admission rate to treat complications. CONCLUSIONS: The present prospective, multicentre study found that 7.6% of elderly patients in China had PICs after elective surgery that could prolong hospital stay and increase 30-day mortality. The clinical effectiveness of admission to critical care after surgery on elderly patients is not identified. Initiatives to increase elderly patients' access to surgical interventions should also enhance safe perioperative care to reduce PICs in China.

CpG postconditioning after reperfused myocardial infarction is associated with modulated inflammation, less apoptosis, and better left ventricular function.

Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). The aim of this study was to investigate whether postconditioning with the cytosine-phosphate-guanine (CpG)-containing Toll-like receptor-9 (TLR9) ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Thirty minutes of left descending coronary artery (LAD) occlusion was conducted in 12-wk-old C57BL/6 mice. Mice were treated with CpG intraperitoneally 5 min before reperfusion. The control group received PBS; the sham group did not undergo ischemia. M-mode echocardiography (3, 7, and 28 days) and Millar left ventricular (LV) catheterization were performed (7 and 28 days) before the hearts were excised and harvested for immunohistochemical (6 h, 24 h, 3 days, 7 days, and 28 days), gene expression (6 h, 24 h, and 3 days; Taqman RT-qPCR), protein, and FACS analysis (24 h and 3 days). Mice treated with CpG showed significantly better LV function after 7 and 28 days of reperfusion. Protein and mRNA expressions of proinflammatory and anti-inflammatory cytokines were significantly induced after CpG treatment. Histology revealed fewer macrophages in CpG mice after 24 h, confirmed by FACS analysis with a decrease in both classically M1- and alternative M2a-monocytes. CpG treatment reduced apoptosis and cardiomyocyte loss and was associated with induction of adaptive mechanisms, e.g., of heme-oxigenase-1 and ß-/α-myosin heavy chain (MHC) ratio. Profibrotic markers collagen type Iα (Col-Ια) and Col-III induction was abrogated in CpG mice, accompanied by fewer myofibroblasts. This led to the formation of a smaller scar. Differential matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a Toll-like receptor 1- and TLR9-dependent manner. Our study suggests a cardioprotective mechanism of CpG postconditioning, involving Toll-like receptor-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV function.NEW & NOTEWORTHY Cytosine-phosphate-guanine (CpG) postconditioning seems to mediate inflammation via Toll-like receptor-1 and Toll-like receptor-9 signaling. Enhanced cytokine and chemokine expressions are partly attenuated by IL-10 and matrix metalloproteinase-8 (MMP8) induction, being associated with lower macrophage infiltration and M1-monocyte differentiation. Furthermore, switch from α- to ß-MHC and balanced MMP/TIMP expression led to lesser cardiomyocyte apoptosis, smaller scar size, and preserved cardiac function. Data of pharmacological postconditioning have been widely disappointing to date. Our study suggests a new pathway promoting myocardial postconditioning via Toll-like receptor activation.

Deficiency of the Transcription Factor NR4A1 Enhances Bacterial Clearance and Prevents Lung Injury During Escherichia Coli Pneumonia.

BACKGROUND: Bacterial pneumonia is one of the most common diagnoses and a leading cause of death in the intensive care unit. NR4A1 is an early response gene that has been identified as a vital regulator of immune and inflammatory responses. This study aims to explore the role of NR4A1 in Escherichia coli (E. coli) pneumonia. METHODS: Alveolar macrophages (AMs) were isolated from wild-type (WT) and NR4A1 knock out (Nr4a1) mice, and the NR4A1 expression and phagocytic capacity against E. coli were measured in vitro. WT and Nr4a1 mice were subjected to E. coli or sham pneumonia. Bacterial load, lung injury severity, inflammatory cell infiltration, and cytokines were assessed at 0, 4, and 18 h after surgery. Survival rates within 48 h were evaluated in WT and Nr4a1 mice. In addition, NR4A1 antagonist (DIM-C-pPhCO2Me) was also used to confirm the role of NR4A1 in vivo and ex vivo. RESULTS: NR4A1 was rapidly induced in AMs at 15 min after E. coli stimulation. Compared with untreated WT AMs, NR4A1 deficiency and DIM-C-pPhCO2Me treatment showed an enhanced phagocytic function (47.72 ±â€Š0.74% vs. 62.3 ±â€Š0.9%, P < 0.001; 11.79 ±â€Š1.21% vs. 30.08 ±â€Š0.79%, P < 0.001, respectively) at 30 min after the E. coli challenge in vitro. NR4A1 deficiency significantly improved the survival rate (33.3% in WT vs. 82.4% in Nr4a1, P < 0.01), which is comparable with DIM-C-pPhCO2Me pretreatment. The survival advantage of Nr4a1 mice was associated with decreased bacterial burden and inflammation and alleviated lung damage. CONCLUSIONS: These data demonstrate that NR4A1 impairs the phagocytic capacity of AMs and disrupts the host defense against invading bacteria, worsening the outcome of E. coli pneumonia in mice.

Low-Copy Number Polymorphism in DEFA1/DEFA3 Is Associated with Susceptibility to Hospital-Acquired Infections in Critically Ill Patients.

DEFA1/DEFA3, genes encoding human neutrophil peptides (HNP) 1-3, display wide-ranging copy number variations (CNVs) and is functionally associated with innate immunity and infections. To identify potential associations between DEFA1/DEFA3 CNV and hospital-acquired infections (HAIs), we enrolled 106 patients with HAIs and 109 controls in the intensive care unit (ICU) and examined their DEFA1/DEFA3 CNVs. DEFA1/DEFA3 copy number ranged from 2 to 16 per diploid genome in all 215 critically ill patients, with a median of 7 copies. In HAIs, DEFA1/DEFA3 CNV varied from 2 to 12 with a median of 6, which was significantly lower than that in controls (2 to 16 with a median of 8, p = 0.017). Patients with lower DEFA1/DEFA3 copy number (CNV < 7) were far more common in HAIs than in controls (52.8% in HAIs versus 35.8% in controls; p = 0.014; OR, 2.010; 95% CI, 1.164-3.472). The area under the receiver operating characteristic (AUROC) of DEFA1/DEFA3 CNV combined with clinical characteristics to predict the incidence of HAIs was 0.763 (95% CI 0.700-0.827), showing strong predictive ability. Therefore, lower DEFA1/DEFA3 copy number contributes to higher susceptibility to HAIs in critically ill patients, and DEFA1/DEFA3 CNV is a significant hereditary factor for predicting HAIs.

Tai Chi Exercise for Patients with Chronic Heart Failure: A Meta-analysis of Randomized Controlled Trials.

AIM: This meta-analysis aimed to update and evaluate evidence from randomized controlled trials of tai chi for patients with chronic heart failure. METHOD: Both English and Chinese databases were searched from their inception to June 2, 2016 (PubMed, EMBASE, Cochrane Central Register of Controlled Trials for English publications and China Knowledge Resource Integrated, Wanfang, and Weipu databases for Chinese publication). Titles, abstracts, and full-text articles were screened against study inclusion criteria: randomized controlled trials studying tai chi intervention for patients with chronic heart failure. The meta-analysis was conducted with Revman 5.3 or STATA 12. RESULT: Thirteen randomized controlled trials were included. Tai chi induced significant improvement in 6-min walking distance (51.01 m; 30.49-71.53; P < 0.00). Moreover, tai chi was beneficial for quality of life (-10.37 points; -14.43 to -6.32; P = 0.00), left ventricular ejection fraction (7.72%; 3.58-11.89; P = 0.003), and B-type natriuretic peptide (-1.01; -1.82 to -0.19; P = 0.02). CONCLUSION: Despite heterogeneity and risk of bias, this meta-analysis further confirms that tai chi may be an effective cardiac rehabilitation method for patients with chronic heart failure. Larger, well-designed randomized controlled trials are needed to exclude the risk of bias.

[Association of single nucleotide polymorphism in exon of transient receptor potential melastatin 2 gene with sepsis].

Objective: To investigate the association between single nucleotide polymorphism (SNP) in the 11th exon of transient receptor potential melastatin 2 (TRPM2) gene with the susceptibility and outcome of sepsis. Methods: A total of 119 septic patients and 112 normal subjects were enrolled from the First Affiliated Hospital, Zhejiang University School of Medicine. Among 119 septic patients, 62 died (fatal group) and 57 survived (survival group) within 28 days of disease onset. The genotypes of these individuals were detected using TaqMan allelic discrimination assays, and its correlations with susceptibility and outcome of sepsis were analyzed. Results: There was no significant difference in genotype frequencies and allelic frequencies of TRPM2 SNP rs1556314 between septic patients and the controls (all P>0.05). And no significant difference in genotype frequencies and allelic frequencies of TRPM2 SNP rs1556314 was observed between the survivors and fatal cases of septic patients (all P>0.05). Conclusion: The TRPM2 SNP rs1556314 does not have significant association with sepsis, but this result need to be confirmed by large scale studies.

Impact of operation timing on post-operative infections following colorectal cancer surgery.

BACKGROUND: To investigate the impact of operation timing on post-operative infections in a cohort of patients undergoing colorectal cancer surgery. METHODS: We prospectively analysed surgical outcomes in patients who underwent colorectal cancer surgery at the First Affiliated Hospital, College of Medicine, Zhejiang University, from January to December in 2014. In this non-randomized trial, patients were divided into three groups according to the surgery start time: CT1 (07:00 to 12:00 h), CT2 (12:01 to 18:00 h), and CT3 (18:01 h to midnight). The primary outcome was the proportion of patients developing infections within 4 weeks of the surgical procedure. RESULTS: Out of 756 patients that were enrolled in the study, 118 developed post-operative infections. The results from blood and pus culture showed 97.1% specimen as being pathogen-free. The overall incidence of post-operative infection was 14.5% (38 of 262), 15.3% (46 of 300) and 17.5% (34 of 194) in the CT1, CT2 and CT3 group, respectively, with no significant inter-group differences. However, white blood cell counts, C-reactive protein and glucose levels at 24 h after the surgical procedure showed significant differences between the three groups (one-way ANOVA, P < 0.05). CONCLUSION: The occurrence of post-operative infection in patients undergoing colorectal cancer surgery was not associated with operation timing. The expression of several inflammatory markers, such as white blood cell counts, C-reactive protein and blood glucose levels tended to correlate with the surgery start time.

Postconditioning with a CpG containing oligodeoxynucleotide ameliorates myocardial infarction in a murine closed-chest model.

AIMS: Toll-like receptor (TLR)9 ligand CpG-oligodeoxynucleotide (CpG-ODN) exerts preconditioning in myocardial ischemia/reperfusion. We hypothesized a postconditioning effect of CpG-ODN in a murine closed-chest model of myocardial infarction. MATERIALS AND METHODS: C57BL/6 (12 weeks, male, WT) mice were instrumented at the left anterior descending artery, then allowed 5d of recovery before 30 min ischemia. Treatments comprised: 1) PBS: 250 µl phosphate buffer solution intraperitoneally 5 min before reperfusion and 2) IPC (ischemic postconditioning): 3 twenty-second reperfusion and occlusion episodes at the end of ischemia 3) CpG-ODN: 1668 thioate 0.2 µmol/kg BW intraperitoneally 5 min before reperfusion. Infarct size was assessed via triphenyltetrazolium chloride (TTC) staining after 2 and 24h reperfusion. Myocardial mRNA-expression of cytokines was measured using real-time PCR after 2h reperfusion. Phosphatidylinositol-3 kinase (PI3K)-inhibitor wortmannin was injected intraperitoneally in WT 15 min before postconditioning and PBS in each group. Cardiac function in WT was assessed with a left-ventricular pressure-volume catheter at 24h reperfusion. KEY FINDINGS: Following 30 min ischemia and 2h reperfusion, infarct size was diminished by 90% in WT postconditioned with CpG-ODN (2.4 ± 1.55 IS/AAR%) and IPC (1.98 ± 1.03 IS/AAR%) compared to PBS mice (23.2 ± 3.97 IS/AAR%). Infarct size increased following 24h reperfusion but the differences remained robust. Expression of TNF-α and IL-10 was increased in CpG-ODN. Wortmannin abolished the postconditioning effect of CpG-ODN and IPC. Ejection fraction and preload-recruitable stroke work were significantly greater in CpG-ODN mice. SIGNIFICANCE: CpG-ODN confers postconditioning via activation of TLR9. Cardiac function is preserved following CpG-ODN postconditioning. The PI3K -inhibitor wortmannin attenuates CpG-ODN postconditioning.

The role of plasma gelsolin in cardiopulmonary bypass induced acute lung injury in infants and young children: a pilot study.

BACKGROUND: Acute lung injury (ALI) induced by cardiopulmonary bypass (CPB, CPB-ALI) is a common and serious complication after cardiac surgery. And infants and young children are more prone to CPB-ALI. The purpose of this study was to investigate the perioperative changes of plasma gelsolin (pGSN) in patients below 3 years of age with cardiac surgeries and CPB, and determine whether pGSN are associated with the occurrence and severity of CPB-ALI. METHODS: Seventy-seven consecutive patients ≤3 years of age with congenital heart diseases (CHD) performed on open heart surgery with CPB were finally enrolled, and assigned to ALI and non-ALI groups according to the American-European Consensus Criteria. Plasma concentrations of gelsolin and total protein were measured at following 8 time points: before CPB (a), after CPB (b), 2 hours after CPB (c), 6 hours after CPB (d), 12 hours after CPB (e), 24 hours after CPB (f), 48 hours after CPB (g) and 72 hours after CPB (h). RESULTS: Twenty-seven (35.1%) patients developed CPB-ALI in the study, including eleven (14.3%) patients with ARDS. The earliest significant drop of pGSN and normalized pGSN (pGSNN) of ALI group both occurred at 6 hours after CPB (p = 0.04 and p < 0.01), which was much earlier than those of non-ALI group (48 hours, p = 0.03 and 24 hours, p < 0.01); PGSN of ALI group before CPB and 6 hours after CPB were both significantly lower than those of non-ALI group (p < 0.01); PGSNN of ALI group before CPB and 6 hours after CPB were both significantly lower than those of non-ALI group (p < 0.01, p = 0.04); PGSN before CPB was the only independent risk factor predicting the occurrence of CPB-ALI (OR, 1.023; 95% CI, 1.007-1.039; p < 0.01) with an AUC of 0.753 (95% CI, 0.626-0.880); The optimal cutoff value of pGSN before CPB was 264.2 mg/L, with a sensitivity of 58.3% and a specificity 94.7%. And lower pGSN before CPB was significantly associated with the severity of CS-AKI (r = -0.45, p < 0.01). CONCLUSIONS: Patients developing CPB-ALI had lower plasma gelsolin reservoir and a much more amount and rapid consumption of plasma gelsolin early after operation. PGSN before CPB was an early and sensitive predictor of CPB-ALI in infants and young children undergoing cardiac surgery, and was negatively correlated with the severity of CPB-ALI.

Polymorphisms of the HTR3B gene are associated with post-surgery emesis in a Chinese Han population.

WHAT IS KNOWN AND OBJECTIVES: The serotoninergic receptor 5-hydroxytryptamine (serotonin) receptor 3 (HTR3) is instrumental in the regulation of nausea and emesis (vomiting).This study investigated whether common genomic variations of the A and B subunits of HTR3 (HTR3A, HTR3B) are associated with the incidence of post-operative vomiting in a Chinese Han population. METHODS: Two hundred and thirty-one female Chinese Han patients undergoing gynaecological surgery with standardized general anaesthesia were recruited for the study. Clinical symptoms after surgery were recorded and direct DNA sequencing was performed to detect polymorphisms of HTR3A and HTR3B. RESULTS: Five single nucleotide polymorphisms (SNPs) in HTR3A and HTR3B were found, with R(2)  > 0·8 and minor allele frequency > 10%. One of these (rs3758987 in HTR3B) was statistically associated with vomiting, after adjusting for body weight, body mass index and duration of general anaesthesia in dominant and additive models (P = 0·047 and P = 0·034). WHAT IS NEW AND CONCLUSION: The HTR3B rs3758987 SNP might serve as a predictor of post-operative vomiting in Chinese Han patients undergoing gynaecological laparoscopic surgery.

Altered melatonin secretion and circadian gene expression with increased proinflammatory cytokine expression in early-stage sepsis patients.

Inflammatory and immune responses, as well as melatonin secretion, are affected by circadian regulation. Abnormal circadian rhythm of melatonin release has been reported to be associated with the later stages of sepsis; however, its role in the early stages of sepsis is unclear. We studied 11 septic and 11 non-septic patients in our intensive care unit (ICU). Peripheral blood was drawn at 4-h intervals on the first day, beginning at 2:00 p.m., over a total period of 24 h. Plasma levels of melatonin, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured by radioimmunoassay or enzyme-linked immunosorbent assay (ELISA). Messenger RNA levels of circadian genes Cry-1 and Per-2 were analyzed using quantitative real-time PCR. Results show the circadian rhythm of melatonin secretion was altered in the early stages of sepsis. The melatonin secretion acrophase occurred earlier in septic patients at 6:00 p.m., compared with at 2:00 a.m. in non-septic ICU patients. Compared with the non-septic group, both Cry-1 and Per-2 expression were significantly decreased while TNF-α and IL-6 expression were significantly increased in septic patients [TNF-α, 64.1 (43.6-89.1) vs. 11.4 (10.4-12.5) ng/ml; IL-6, 41.2 (35.7-50.8) vs. 19.1 (16-136.7) ng/ml; median (range), both P=0.04]. The peak concentrations of TNF-α and IL-6 were shown to be in concordance with the rhythm of melatonin secretion. The circadian rhythm of melatonin secretion and circadian gene expression were altered in the early stages of sepsis, which likely led to the changes in pro-inflammatory cytokine release. These findings shed light on the potential link between circadian rhythm and the progression of early-stage sepsis.

[The effect of two methods guided fluid therapy to the patient undergoing open gastrointestinal surgery].

OBJECTIVE: To investigate the effect of central venous blood oxygen saturation (ScvO2) and venous-arterial PCO2 (P(cv-a)CO2) guided fluid therapy on tissue perfusion, gastrointestinal function recovering and outcome of the patients who undergoing open gastrointestinal surgery. METHODS: Forty patients undergoing open gastrointestinal surgery were randomly divided into 2 groups (n = 20 each): ScvO2 guided fluid therapy (group S) and P(cv-a) CO2 guided fluid therapy (group P). All the patients were infused 10 ml/kg lactated Ringer's (LR) solution before anesthesia induction, they were all also given a continuous lactated Ringer's (LR) solution's infusion at the speed of 2 ml·kg(-1)·h(-1) during the operation. While, 6%HES 130/0.4 (free flex 6%HES 130/0.4, Fresenius Kabi) infusion was different between the 2 groups, when the patients of group S's central venous blood oxygen saturation < 75% or venous-arterial PCO2 in the patients of P group ≥6 mm Hg, then infused 6%HES 130/0.4. Arterial and central venous blood gas analyses were performed every 20 minutes after skin incision, measure the venous and arterial lactate value, and record the anal exhaust time after surgery, postoperative complications and mortality in 28 days. RESULTS: Compared with group S, the arterial lactate value in T4 (after operation began 80 min) were significantly decreased in group P (P = 0.013), and venous lactate value in T5 (after operation began 100 min) were also lower (P = 0.044), other lactate value were not different (P > 0.05) . The anal exhaust time was not different between the two groups (P = 0.673). All the patients were survival, and there were no obvious postoperative complications. CONCLUSION: Compared to group S, there was a transient improvement in tissue perfusion in group P, but there were no difference in complications and mortality.

Nuclear factor-κB mediated lipopolysaccharide-induced mRNA expression of hepcidin in human peripheral blood leukocytes.

Hepcidin is a known key modulator of iron homeostasis and an innate immune molecule secreted by the liver. The transcriptional mechanism of hepcidin in hepatocytes during inflammation is mediated via the IL-6/STAT3 pathway. Recently, hepcidin demonstrated an anti-inflammatory function in endotoxic mice, and a TLR4-dependent inducible expression of hepcidin was detected in myeloid cells. In this study, we explored the expression and signaling mechanism regulating hepcidin mRNA expression in peripheral blood leukocytes. The mRNA levels of hepcidin in peripheral blood leukocytes from patients with severe sepsis (n = 14) was significantly higher than those in healthy controls (n = 16;0.286 ± 0.065 vs 0.068 ± 0.025; P < 0.05). Ex vivo studies found hepcidin mRNA can be highly induced by challenge of 100 ng/ml LPS or 20 ng/ml TNF-α in peripheral blood leukocytes rather than IL-6, IL-1 and IFN-γ. Anti-TNF-α antibody significantly decreased the levels of hepcidin mRNA induced by LPS. Inhibitor of nuclear factor (NF)-κB rather than that of STAT3 completely abolished the inducibility of hepcidin mRNA in PBMCs and neutrophils. These results indicate that hepcidin mRNA expression in peripheral blood leukocytes induced by LPS depends on NF-κB, and TNF-α may be a key mediator in this procedure.

Increased genomic copy number of DEFA1/DEFA3 is associated with susceptibility to severe sepsis in Chinese Han population.

BACKGROUND: Human neutrophil peptides 1-3 are endogenous cationic antimicrobial peptides implicated in host defense against microbes. The genes encoding human neutrophil peptides 1-3 (DEFA1/DEFA3) exhibit copy number variations. This study was designed to determine whether DEFA1/DEFA3 copy number variations conferred susceptibility to infection-induced complications such as severe sepsis. METHODS: This case-control study was performed in 179 patients with severe sepsis and 233 healthy blood donors and was replicated in an independent cohort of 112 cases and 118 controls. Plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 were detected. RESULTS: The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis than in controls (55.9% vs. 31.3%; P = 1.13 x 10, odds ratio 2.77, 95% confidence interval 1.85-4.16). After adjustment for age and gender, logistic regression analysis confirmed the association of the genotype of more than eight copies with an increased risk of severe sepsis (P = 2.25 x 10, odds ratio 2.66, 95% confidence interval 1.69-4.19). This established association was replicated in a second age- and gender-matched case-control cohort (P = 0.02, odds ratio 1.90, 95% confidence interval 1.11-3.27). Furthermore, compared with those with fewer copies, the patients carrying more than eight copies of DEFA1/DEFA3 presented significantly lower plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively). CONCLUSIONS: DEFA1/DEFA3 is an important genetic component participating in host immune response to severe sepsis. A higher copy number of DEFA1/DEFA3 (>8 copies) is significantly associated with the risk of severe sepsis.

[Comparison of three different organ failure assessment score systems in predicting outcome of severe sepsis].

OBJECTIVE: To compare multiple organ dysfunction score (MODS), the sequential organ failure assessment (SOFA) and the logistic organ dysfunction score (LODS) in predicting hospital mortality in severe sepsis. METHODS: Four hundred and three patients admitted to the ICU from December 2004 to November 2007 with a diagnosis of severe sepsis were enrolled in this study. Their MODS, SOFA, LODS and Acute Physiology and Chronic Health Evaluation (APACHE) II at admission and the highest score during hospitalization were respectively recorded and collected in regard to mortality. The discrimination of three multiple organ dysfunction score systems were assessed by the areas under the receiver operating characteristic curves (AUC). RESULTS: The AUC of admission scores was 0.811 for LODS, 0.787 for SOFA, 0.725 for MODS, and 0.770 for APACHE II in predicting hospital mortality. All maximum scores had better power of discrimination than the admission scores (P < 0.01). The power of discrimination of LODS and SOFA were better than the MODS, either the admission or the highest, respectively (P < 0.01). However, no significant difference was observed between the LODS and the SOFA regarding mortality prediction (P > 0.05). The AUC value for the APACHE II score was much lower compared to LODS (P < 0.01). However, there was no difference in AUC value among APACHE II, SOFA and MODS (P > 0.05). CONCLUSION: LODS, SOFA and MODS show a good discrimination power, while maximum LODS is of the highest discrimination power to predict the outcome of patient with severe sepsis.

Time course of plasma gelsolin concentrations during severe sepsis in critically ill surgical patients.

INTRODUCTION: Gelsolin is an actin-binding plasma protein that is part of an 'actin-scavenging' system. Studies suggest that plasma gelsolin may play a crucial role in the pathophysiology of sepsis. Little is known about the course of plasma gelsolin levels over time in patients with severe sepsis. The aim of the study was to investigate plasma gelsolin levels in severe septic patients and to determine whether these levels predict the severity or clinical outcome of severe sepsis. METHODS: Ninety-one patients who were diagnosed with severe sepsis at admission to a surgical intensive care unit were enrolled, and admission plasma gelsolin levels were recorded. Plasma gelsolin levels were recorded daily in 23 of these patients. Daily plasma gelsolin levels were recorded in an additional 15 nonseptic critically ill patients. Fifteen volunteers served as healthy control individuals. Plasma gelsolin levels were measured using an enzyme-linked immunosorbent assay. Concentrations of IL-6, IL-10 and tumour necrosis factor (TNF)-alpha were also measured on intensive care unit admission. RESULTS: The admission gelsolin levels were significantly decreased in severe sepsis (20.6 +/- 11.7 mg/l) compared with nonseptic critically ill patients (52.3 +/- 20.3 mg/l; P < 0.001) and healthy control individuals (126.8 +/- 32.0 mg/l; P < 0.001). Severe septic patients had increased IL-6 levels compared with nonseptic critically ill patients (20.0 +/- 10.7 pg/ml versus 11.4 +/- 13.9 pg/ml; P = 0.048), whereas no significant difference in IL-10 or TNF-alpha levels was observed (IL-10: 97.9 +/- 181.5 pg/ml versus 47.4 +/- 91.5 pg/ml, respectively [P = 0.425]; TNF-alpha: 14.2 +/- 13.9 pg/ml versus 6.9 +/- 5.3 pg/ml, respectively; P = 0.132). Survivors of severe sepsis exhibited substantial recovery of their depressed plasma gelsolin levels, whereas gelsolin levels in nonsurvivors remained at or below their depleted admission levels. CONCLUSION: Plasma gelsolin may be a valuable marker for severe sepsis. Recovery of depleted plasma gelsolin levels correlated with clinical improvement. The prognostic role of plasma gelsolin in critical illness requires further investigation in a large cohort.