Lipopolysaccharide-induced Notch signaling activation through JNK-dependent pathway regulates inflammatory response

Background  

Notch and TLR pathways were found to act cooperatively to activate Notch target genes and to increase the production of TLR-induced cytokines in macrophages. However, the mechanism of LPS-induced Notch activation and its role in sepsis still remains unclear.     

Evolution of the Kdo<Subscript>2</Subscript>-lipid A biosynthesis in bacteria

Background  

Lipid A is the highly immunoreactive endotoxic center of lipopolysaccharide (LPS). It anchors the LPS into the outer membrane of most Gram-negative bacteria. Lipid A can be recognized by animal cells, triggers defense-related responses, and causes Gram-negative sepsis. The biosynthesis of Kdo₂-lipid A, the LPS substructure, involves with nine enzymatic steps.     

Genetic islands of <Emphasis Type="Italic">Streptococcus agalactiae</Emphasis> strains NEM316 and 2603VR and their presence in other Group B Streptococcal strains

Background  

Streptococcus agalactiae (Group B Streptococcus; GBS) is a major contributor to obstetric and neonatal bacterial sepsis. Serotype III strains cause the majority of late-onset sepsis and meningitis in babies, and thus appear to have an enhanced invasive capacity compared with the other serotypes that cause disease predominantly in immunocompromised pregnant women. We compared the serotype III and V whole genome sequences, strains NEM316 and 2603VR respectively, in an attempt to identify genetic attributes of strain NEM316 that might explain the propensity of strain NEM316 to cause late-onset disease in babies. Fourteen putative pathogenicity islands were described in the strain NEM316 whole genome sequence. Using PCR- and targeted microarray- strategies, the presence of these islands were assessed in a diverse strain collection including 18 colonizing isolates from healthy pregnant women, and 13 and 8 invasive isolates from infants with early- and late-onset sepsis, respectively.     

The Effect of Hospital Volume on Mortality in Patients Admitted with Severe Sepsis

Importance

The association between hospital volume and inpatient mortality for severe sepsis is unclear.

Objective

To assess the effect of severe sepsis case volume and inpatient mortality.

Design Setting and Participants

Retrospective cohort study from 646,988 patient discharges with severe sepsis from 3,487 hospitals in the Nationwide Inpatient Sample from 2002 to 2011.

Exposures

The exposure of interest was the mean yearly sepsis case volume per hospital divided into tertiles.

Main Outcomes and Measures

Inpatient mortality.

Results

Compared with the highest tertile of severe sepsis volume (>60 cases per year), the odds ratio for inpatient mortality among persons admitted to hospitals in the lowest tertile (≤10 severe sepsis cases per year) was 1.188 (95% CI: 1.074–1.315), while the odds ratio was 1.090 (95% CI: 1.031–1.152) for patients admitted to hospitals in the middle tertile. Similarly, improved survival was seen across the tertiles with an adjusted inpatient mortality incidence of 35.81 (95% CI: 33.64–38.03) for hospitals with the lowest volume of severe sepsis cases and a drop to 32.07 (95% CI: 31.51–32.64) for hospitals with the highest volume.

Conclusions and Relevance

We demonstrate an association between a higher severe sepsis case volume and decreased mortality. The need for a systems-based approach for improved outcomes may require a high volume of severely septic patients.     

Adhesive properties of Enterobacter sakazakii to human epithelial and brain microvascular endothelial cells

Background  

Enterobacter sakazakii is an opportunistic pathogen that has been associated with sporadic cases and outbreaks causing meningitis, necrotizing enterocolitis and sepsis especially in neonates. However, up to now little is known about the mechanisms of pathogenicity in E. sakazakii. A necessary state in the successful colonization, establishment and ultimately production of disease by microbial pathogens is the ability to adhere to host surfaces such as mucous membranes, gastric and intestinal epithelial or endothelial tissue.     

The signature of long-standing balancing selection at the human defensin β-1 promoter

Background  

Defensins, small endogenous peptides with antimicrobial activity, are pivotal components of the innate immune response. A large cluster of defensin genes is located on human chromosome 8p; among them the beta defensin 1 (DEFB1) promoterhas been extensively studied since discovery that specific polymorphisms and haplotypes associate with asthma and atopy, susceptibility to severe sepsis, as well as HIV and Candida infection predisposition.     

Classification of the extracellular fields produced by activated neural structures

Background  

Classifying the types of extracellular potentials recorded when neural structures are activated is an important component in understanding nerve pathophysiology. Varying definitions and approaches to understanding the factors that influence the potentials recorded during neural activity have made this issue complex.     

Long Term Health-Related Quality of Life in Survivors of Sepsis in South West Wales: An Epidemiological Study

Introduction

Survivors of sepsis report persistent problems that can last years after hospital discharge. The main aim of this study was to investigate long-term health-related quality of life in survivors of SIRS and sepsis compared with Welsh normative data, controlling for age, length of stay and pre-existing conditions. The second aim was to investigate any differences in long-term health-related quality of life specifically with the patients categorised into three groups; SIRS, uncomplicated sepsis and severe sepsis/septic shock.

Methods

A prospective study design was used in order to investigate all sepsis patients either presenting to the Emergency Department or admitted to the Intensive Care Unit of a regional trauma centre. Baseline demographics, clinical characteristics and outcomes were collected and surviving patients were sent a SF-12v2 survey at between six months to two years post-hospital discharge.

Results

Quality of life was significantly reduced in all patients when compared to local normative data (all p<0.0001). Reductions in the physical components of health-related quality of life were more pronounced in severe sepsis/septic shock patients when compared to uncomplicated sepsis and SIRS patients, when controlling for age, pre-existing conditions, hospital and ICU length of stay.

Conclusions

This is the first observational study to specifically focus on the different groups of SIRS and sepsis patients to assess long-term quality of life. Local population norms were used for comparison, rather than UK-wide norms that fail to reflect the intricacies of a country’s population.     

BioPhysConnectoR: Connecting Sequence Information and Biophysical Models

Background  

One of the most challenging aspects of biomolecular systems is the understanding of the coevolution in and among the molecule(s).     

Rhabdomyolysis in Community Acquired Bacterial Sepsis – A Retrospective Cohort Study

Background and Objectives

Rhabdomyolysis is often associated with sepsis and gram positive bacterial pathogens are reported to be the most frequent cause of sepsis induced rhabdomyolysis. We report the pattern of infecting bacterial pathogens and associated causal factors in a South-Indian cohort.

Design, Setting, Participants & Measurements

Retrospective cohort study of adult patients with community acquired bacterial sepsis complicated by rhabdomyolysis from March 2003 - August 2008. Rhabdomyolysis was defined as serum creatine kinase >2000 IU/L. The study population was divided into group-I (sepsis with gram positive pathogens), group–II (sepsis with gram negative pathogens) and group-III (culture negative sepsis).

Results

103 patients (group I -15, group II- 34 and group III- 54) formed the study cohort. Mean age was 55 years and two-third had diabetes. Mean creatine kinase was 7114 IU/L and mean serum creatinine on admission was 2.4 mg/dl. Causative pathogen of sepsis was identified in 47.5%. Gram negative pathogens were more frequently (33%) associated with rhabdomyolysis than gram positive pathogens (14.5%). Lung was the commonest foci of sepsis (38.8%). 78.6% of the study population had one or more additional causal factor for rhabdomyolysis like statin intake, chronic alcoholism, hypokalemia, hypernatremia and hypophosphatemia. Mortality was 59%.

Conclusions

Gram negative bacterial pathogens were more frequently associated with rhabdomyolysis than gram positive pathogens. Rhabdomyolysis in patients with sepsis is multifactorial and is associated with high mortality.     

Decreased levels of the gelsolin plasma isoform in patients with rheumatoid arthritis

Introduction  

Gelsolin is an intracellular actin-binding protein involved in cell shape changes, cell motility, and apoptosis. An extracellular gelsolin isoform, plasma gelsolin circulates in the blood of healthy individuals at a concentration of 200 ± 50 mg/L and has been suggested to be a key component of an extracellular actin-scavenging system during tissue damage. Levels of plasma gelsolin decrease during acute injury and inflammation, and administration of recombinant plasma gelsolin to animals improves outcomes following sepsis or burn injuries. In the present study, we investigated plasma gelsolin in patients with rheumatoid arthritis.     

A complex endeavour: an ethnographic study of the implementation of the Sepsis Six clinical care bundle

Background

Implementation of the ‘Sepsis Six’ clinical care bundle within an hour of recognition of sepsis is recommended as an approach to reduce mortality in patients with sepsis, but achieving reliable delivery of the bundle has proved challenging. There remains little understanding of the barriers to reliable implementation of bundle components. We examined frontline clinical practice in implementing the Sepsis Six.

Methods

We conducted an ethnographic study in six hospitals participating in the Scottish Patient Safety Programme Sepsis collaborative. We conducted around 300 h of non-participant observation in emergency departments, acute medical receiving units and medical and surgical wards. We interviewed a purposive sample of 43 members of hospital staff. Data were analysed using a constant comparative approach.

Results

Implementation strategies to promote reliable use of the Sepsis Six primarily focused on education, engaging and motivating staff, and providing prompts for behaviour, along with efforts to ensure that equipment required was readily available. Although these strategies were successful in raising staff awareness of sepsis and engagement with implementation, our study identified that completing the bundle within an hour was not straightforward. Our emergent theory suggested that rather than being an apparently simple sequence of six steps, the Sepsis Six actually involved a complex trajectory comprising multiple interdependent tasks that required prioritisation and scheduling, and which was prone to problems of coordination and operational failures. Interventions that involved allocating specific roles and responsibilities for completing the Sepsis Six in ways that reduced the need for coordination and task switching, and the use of process mapping to identify system failures along the trajectory, could help mitigate against some of these problems.

Conclusions

Implementation efforts that focus on individual behaviour change to improve uptake of the Sepsis Six should be supplemented by an understanding of the bundle as a complex trajectory of work in which improving reliability requires attention to coordination of workflow, as well as addressing the mundane problems of interruptions and operational failures that obstruct task completion.

     

Development of real-time PCR for detection of <Emphasis Type="Italic">Mycoplasma hominis</Emphasis>

Background  

Mycoplasma hominis is associated with pelvic inflammatory disease, bacterial vaginosis, post partum fever, sepsis and infections of the central nervous system often leading to serious conditions. Association with development of female infertility has also been suggested, but different publications present different results. We developed a sensitive and fast diagnostic real-time PCR to test clinical samples from women undergoing laparoscopic examination before fertility treatment. To develop a test for the detection and quantification of M. hominis we selected a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (gap), as a target.     

The Impact of Nationwide Education Program on Clinical Practice in Sepsis Care and Mortality of Severe Sepsis: A Population-Based Study in Taiwan

Objectives

We investigated the effect of a nationwide educational program following surviving sepsis campaign (SSC) guidelines. Physicians’ clinical practice in sepsis care and patient mortality rate for severe sepsis were analyzed using a nationally representative cohort.

Methods

Hospitalizations for severe sepsis with organ failure from 1997 to 2008 were extracted from Taiwan’s National Health Insurance Research Database (NHIRD), and trends in sepsis incidence and mortality rates were analyzed. A before-and-after study design was used to evaluate changes in the utilization rates of SSC items and changes in severe sepsis mortality rates occurred after a national education program conducted by the Joint Taiwan Critical Care Medicine Committee since 2004. A total of 39,706 hospitalizations were analyzed, which consisted of a pre-intervention cohort of 14,848 individuals (2000-2003) and a post-intervention cohort of 24,858 individuals (2005-2008).

Results

The incidence rate of severe sepsis increased from 1.88 per 1,000 individuals in 1997 to 5.07 per 1,000 individuals in 2008. The cumulative mortality rate decreased slightly from 48.2% for the pre-intervention cohort to 45.9% for the post-intervention cohort. The utilization rates of almost all SSC items changed significantly between the pre-intervention and post-intervention cohorts. These changes of utilization rates were found to be associated with mild reduction in mortality rate.

Conclusion

The nationwide education program through a national professional society has a significant impact on physicians’ clinical practice and resulted in a slight but significant reduction of severe sepsis mortality rate.     

Blood lactate levels in 31 female dogs with pyometra

Background  

Canine pyometra is a life-threatening disease common in countries where spaying of dogs is not routinely performed. The disease is associated with endotoxemia, sepsis, systemic inflammatory response syndrome (SIRS) and a 3–4% mortality rate. Blood lactate analysis is clinically valuable in predicting prognosis and survival, evaluating tissue perfusion and treatment response in human and veterinary critical care settings. The aims of the present study were to investigate 1) the blood lactate levels of female dogs with pyometra by a hand-held analyser and 2) if these levels are related with the clinical status or other biochemical or hematological disorders.     

Sustained Elevation of Resistin,NGAL and IL-8 Are Associated with Severe Sepsis/Septic Shock in the Emergency Department

Objective

To identify biomarkers which distinguish severe sepsis/septic shock from uncomplicated sepsis in the Emergency Department (ED).

Methods

Patients with sepsis underwent serial blood sampling, including arrival in the ED and up to three subsequent time points over the first 24 hours. Messenger RNA (mRNA) levels of 13 genes representing arms of the innate immune response, organ dysfunction or shock were measured in peripheral blood leucocytes using quantitative PCR, and compared with healthy controls. Serum protein concentrations of targets differentially expressed between uncomplicated sepsis and severe sepsis/septic shock were then measured at each time point and compared between the two patient groups.

Results

Of 27 participants (median age 66 years, (IQR 35, 78)), 10 had uncomplicated sepsis and 17 had sepsis with organ failure (14 septic shock; 3 had other sepsis-related organ failures). At the time of first sample collection in the ED, gene expression of Interleukin (IL)-10 and Neutrophil Gelatinase Associated Lipocalin (NGAL) were significantly higher in severe sepsis than uncomplicated sepsis. Expression did not significantly change over time for any target gene. Serum concentrations of IL-6, IL-8, IL-10, NGAL and Resistin were significantly higher in severe sepsis than uncomplicated sepsis at the time of first sample collection in the ED, but only IL-8, NGAL and Resistin were consistently higher in severe sepsis compared to uncomplicated sepsis at all time points up to 24 h after presentation.

Conclusions

These mediators, produced by both damaged tissues and circulating leukocytes, may have important roles in the development of severe sepsis. Further work will determine whether they have any value, in addition to clinical risk parameters, for the early identification of patients that will subsequently deteriorate and/or have a higher risk of death.     

Platelets Induce Apoptosis during Sepsis in a Contact-Dependent Manner That Is Inhibited by GPIIb/IIIa Blockade

Purpose

End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS), especially where platelets accumulate (e.g. spleen and lung). We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease granzyme B. We now aim to define the site(s) of and mechanism(s) by which platelet granzyme B induces end-organ apoptosis in sepsis.

Methods

End-organ apoptosis in murine sepsis (i.e. polymicrobial peritonitis) was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90 minute ex vivo co-incubation with healthy murine splenocytes. Sepsis progression was measured via validated preclinical murine sepsis score.

Measurements and Main Results

There was evident apoptosis in spleen, lung, and kidney sections from septic wild type mice. In contrast, there was a lack of TUNEL staining in spleens and lungs from septic granzyme B null mice and these mice survived longer following induction of sepsis than wild type mice. In co-incubation experiments, physical separation of septic platelets from splenocytes by a semi-permeable membrane reduced splenocyte apoptosis to a rate indistinguishable from negative controls. Chemical separation by the platelet GPIIb/IIIa receptor inhibitor eptifibatide decreased apoptosis by 66.6±10.6% (p = 0.008). Mice treated with eptifibatide in vivo survived longer following induction of sepsis than vehicle control mice.

Conclusions

In sepsis, platelet granzyme B-mediated apoptosis occurs in spleen and lung, and absence of granzyme B slows sepsis progression. This process proceeds in a contact-dependent manner that is inhibited ex vivo and in vivo by the platelet GPIIb/IIIa receptor inhibitor eptifibatide. The GPIIb/IIIa inhibitors and other classes of anti-platelet drugs may be protective in sepsis.     

Walk-weighted subsequence kernels for protein-protein interaction extraction

Background  

The construction of interaction networks between proteins is central to understanding the underlying biological processes. However, since many useful relations are excluded in databases and remain hidden in raw text, a study on automatic interaction extraction from text is important in bioinformatics field.     

C5a Regulates IL-12+DC Migration to Induce Pathogenic Th1 and Th17 Cells in Sepsis

Objective

It is well known that complement system C5a is excessively activated during the onset of sepsis. However, it is unclear whether C5a can regulate dentritic cells (DCs) to stimulate adaptive immune cells such as Th1 and Th17 in sepsis.

Methods

Sepsis was induced by cecal ligation and puncture (CLP). CLP-induced sepsis was treated with anti-C5a or IL-12. IL-12⁺DC, IFNγ⁺Th1, and IL-17⁺Th17 cells were analyzed by flow cytometry. IL-12 was measured by ELISA.

Results

Our studies here showed that C5a induced IL-12⁺DC cell migration from the peritoneal cavity to peripheral blood and lymph nodes. Furthermore, IL-12⁺DC cells induced the expansion of pathogenic IFNγ⁺Th1 and IL-17⁺Th17 cells in peripheral blood and lymph nodes. Moreover, IL-12, secreted by DC cells in the peritoneal cavity, is an important factor that prevents the development of sepsis.

Conclusion

Our data suggests that C5a regulates IL-12⁺DC cell migration to induce pathogenic Th1 and Th17 cells in sepsis.