Natural Killer Cell Alloreactivity Against Human Induced Pluripotent Stem Cells and Their Neuronal Derivatives into Dopaminergic Neurons

In recent years, great hope has arisen surrounding human stem cells, particularly human induced pluripotent stem (hiPS) cells, as nearly all human tissues can be derived from hiPS cells, using a specific protocol. Therefore, hiPS cells can be a source for replacing defective tissues and make up for the lack of organ donors. However, the alloreactivity of hiPS cells and their derivatives in the context of transplantation remain unclear. Although immunosuppressive drugs can inhibit the T cell compartment, these drugs inhibit partially or not at all natural killer (NK) cells activity. Therefore, the alloreactivity of NK cells against transplanted cells remains to be established. To partially answer this question, we choose, as a model, the potential of cellular therapy for Parkinson's disease (PD). First, we established the in vitro derivation of hiPS cells into mature dopaminergic (mDOPA) neurons, going through an intermediate step called neurosphere (NS) cells. These different cells population were cultured with or without interferon gamma (IFN-γ). They were characterized phenotypically regarding their morphology, and the expression of specific ligands for NK cell receptors expressed by these cells types was investigated. NK cells were isolated from the peripheral blood of healthy donors and cultured in the presence of interleukin 15, to be activated. To test NK cell alloreactivity, a cytotoxic assay was performed with hiPS cells, NS cells, and mDOPA neurons (IFN-γ treated or not) cocultured with allogenic NK cells. Our results show that allogenic NK cells kill hiPS cells (IFN-γ treated or not), but IFN-γ-treated NS cells were protected from killing by allogenic NK cells, compared with untreated NS cells. Finally, mDOPA neurons (IFN-γ treated or not) were partially protected against allogenic NK cell killing. These results indicate that derivatives of hiPS cells, especially NS cells, could be a good product for allogenic transplantation in cellular therapy for PD

Epidemiology, management and risk factors for death of invasive Candida infections in critical care units: a multicenter, prospective, observational study in France (2005-2006)

International audienceOBJECTIVE: To describe the evolving epidemiology, management, and risk factors for death of invasive Candida infections in intensive care units (ICUs). DESIGN: Prospective, observational, national, multicenter study. SETTING: One hundred eighty ICUs in France. PATIENTS: Between October 2005 and May 2006, 300 adult patients with proven invasive Candida infection who received systemic antifungal therapy were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred seven patients (39.5%) with isolated candidemia, 87 (32.1%) with invasive candidiasis without documented candidemia, and 77 (28.4%) with invasive candidiasis and candidemia were eligible. In 37% of the cases, candidemia occurred within the first 5 days after ICU admission. C. albicans accounted for 57.0% of the isolates, followed by C. glabrata (16.7%), C. parapsilosis (7.5%), C. krusei (5.2%), and C. tropicalis (4.9%). In 17.1% of the isolates, the causative Candida was less susceptible or resistant to fluconazole. Fluconazole was the empirical treatment most commonly introduced (65.7%), followed by caspofungin (18.1%), voriconazole (5.5%), and amphotericin B (3.7%). After identification of the causative species and susceptibility testing results, treatment was modified in 86 patients (31.7%). The case fatality ratio in ICU was 45.9% and did not differ significantly according to the type of episode. Multivariate analysis showed that factors independently associated with death in ICU were type 1 diabetes mellitus (odds ratio [OR] 4.51; 95% confidence interval [CI] 1.72-11.79; p = 0.002), immunosuppression (OR 2.63; 95% CI 1.35-5.11; p = 0.0045), mechanical ventilation (OR 2.54; 95% CI 1.33-4.82; p = 0.0045), and body temperature >38.2 degrees C (reference, 36.5-38.2 degrees C; OR 0.36; 95% CI 0.17-0.77; p = 0.008). CONCLUSIONS: More than two thirds of patients with invasive candidiasis in ICU present with candidemia. Non-albicans Candida species reach almost half of the Candida isolates. Reduced susceptibility to fluconazole is observed in 17.1% of Candida isolates. Mortality of invasive candidiasis in ICU remains high

Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study.

OBJECTIVE: To investigate community-acquired pneumonia (CAP) as a cause of severe sepsis in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial and to evaluate the effect of drotrecogin alfa (activated) (DrotAA) in this subgroup. DESIGN: Retrospective analysis of the severe CAP subgroup in the PROWESS trial. SETTING: Tertiary care institutions in 11 countries. INTERVENTIONS: DrotAA (n = 850), 24 microg.kg.hr for 96 hrs, or placebo (n = 840). PARTICIPANTS: The 1,690 patients with severe sepsis enrolled in the PROWESS trial. MEASUREMENTS AND MAIN RESULTS: Patients were classified as having CAP if lung was the primary site of infection and if they were enrolled directly from home (private residence) with /=25, Pneumonia Severity Index score of >/=4, or CURB-65 (confusion, urea, respiratory rate, blood pressure, age) score of >/=3. CONCLUSIONS: CAP associated with a high Pneumonia Severity Index score, bacteremia, or an intense coagulation and inflammatory response requiring intensive care unit care were indicators of a high risk of death from severe sepsis. In patients with severe sepsis resulting from CAP, a readily identifiable disease, DrotAA, improved survival compared with placebo

O-Antigen Targeted Vaccines Against Escherichia coli May Be Useful in Reducing Morbidity, Mortality, and Antimicrobial Resistance

International audienc

Comparison of European ICU patients in 2012 (ICON) versus 2002 (SOAP)

Purpose: To evaluate differences in the characteristics and outcomes of intensive care unit (ICU) patients over time. Methods: We reviewed all epidemiological data, including comorbidities, types and severity of organ failure, interventions, lengths of stay and outcome, for patients from the Sepsis Occurrence in Acutely ill Patients (SOAP) study, an observational study conducted in European intensive care units in 2002, and the Intensive Care Over Nations (ICON) audit, a survey of intensive care unit patients conducted in 2012. Results: We compared the 3147 patients from the SOAP study with the 4852 patients from the ICON audit admitted to intensive care units in the same countries as those in the SOAP study. The ICON patients were older (62.5 ± 17.0 vs. 60.6 ± 17.4 years) and had higher severity scores than the SOAP patients. The proportion of patients with sepsis at any time during the intensive care unit stay was slightly higher in the ICON study (31.9 vs. 29.6%, p = 0.03). In multilevel analysis, the adjusted odds of ICU mortality were significantly lower for ICON patients than for SOAP patients, particularly in patients with sepsis [OR 0.45 (0.35–0.59), p < 0.001]. Conclusions: Over the 10-year period between 2002 and 2012, the proportion of patients with sepsis admitted to European ICUs remained relatively stable, but the severity of disease increased. In multilevel analysis, the odds of ICU mortality were lower in our 2012 cohort compared to our 2002 cohort, particularly in patients with sepsis. © 2018, The Author(s)