CCL18 Exhibits a Regulatory Role through Inhibition of Receptor and Glycosaminoglycan Binding

CCL18 has been reported to be present constitutively at high levels in the circulation, and is further elevated during inflammatory diseases. Since it is a rather poor chemoattractant, we wondered if it may have a regulatory role. CCL18 has been reported to inhibit cellular recruitment mediated by CCR3, and we have shown that whilst it is a competitive functional antagonist as assessed by Schild plot analysis, it only binds to a subset of CCR3 receptor populations. We have extended this inhibitory activity to other receptors and have shown that CCL18 is able to inhibit CCR1, CCR2, CCR4 and CCR5 mediated chemotaxis, but has no effect on CCR7 and CCR9, nor the CXC receptors that we have tested. Whilst CCL18 is able to bind to CCR3, it does not bind to the other receptors that it inhibits. We therefore tested the hypothesis that it may displace glycosaminoglycan (GAG) chemokines bound either in cis- on the leukocyte, or in trans-presentation on the endothelial surface, thereby inhibiting the recruitment of leukocytes into the site of inflammation. We show that CCL18 selectivity displaces heparin bound chemokines, and that chemokines from all four chemokine sub-classes displace cell bound CCL18. We propose that CCL18 has regulatory properties inhibiting chemokine function when GAG-mediated presentation plays a role in receptor activation.     

Refining the Plasmid-Encoded Type IV Secretion System Substrate Repertoire of Coxiella burnetii

The intracellular bacterial agent of Q fever, Coxiella burnetii, translocates effector proteins into its host cell cytosol via a Dot/Icm type IV secretion system (T4SS). The T4SS is essential for parasitophorous vacuole formation, intracellular replication, and inhibition of host cell death, but the effectors mediating these events remain largely undefined. Six Dot/Icm substrate-encoding genes were recently discovered on the C. burnetii cryptic QpH1 plasmid, three of which are conserved among all C. burnetii isolates, suggesting that they are critical for conserved pathogen functions. However, the remaining hypothetical proteins encoded by plasmid genes have not been assessed for their potential as T4SS substrates. In the current study, we further defined the T4SS effector repertoire encoded by the C. burnetii QpH1, QpRS, and QpDG plasmids that were originally isolated from acute-disease, chronic-disease, and severely attenuated isolates, respectively. Hypothetical proteins, including those specific to QpRS or QpDG, were screened for translocation using the well-established Legionella pneumophila T4SS secretion model. In total, six novel plasmid-encoded proteins were translocated into macrophage-like cells by the Dot/Icm T4SS. Four newly identified effectors are encoded by genes present only on the QpDG plasmid from severely attenuated Dugway isolates, suggesting that the presence of specific effectors correlates with decreased virulence. These results further support the idea of a critical role for extrachromosomal elements in C. burnetii pathogenesis.     

Short-term temperature impact on soil heterotrophic respiration in limed agricultural soil samples

This study sought to investigate the hourly and daily timescale responses of soil CO₂ fluxes to temperature in a limed agricultural soil. Observations from different incubation experiments were compared with the results of a model combining biotic (heterotrophic respiration) and abiotic (carbonate weathering) components. Several samples were pre-incubated for 8–9 days at three temperatures (5, 15 and 25 °C) and then submitted to short-term temperature (STT) cycles (where the temperature was increased from 5 to 35 °C in 10 °C stages, with each stage being 3 h long). During the temperature cycles (hourly timescale), the soil CO₂ fluxes increased significantly with temperature under all pre-incubation temperature (PIT) treatments. A hysteresis effect and negative fluxes during cooling phases were also systematically observed. At a given hourly timescale temperature, there was a negative relationship of the CO₂ fluxes with the PIT. Using the combined model allowed the experimental results to be clearly described, including the negative fluxes and the hysteresis effect, showing the potentially large contribution of abiotic fluxes to total fluxes in limed soils, after STT changes. The fairly good agreement between the measured and simulated flux results also suggested that the biotic flux temperature sensitivity was probably unaffected by timescale (hourly or daily) or PIT. The negative relationship of the CO₂ fluxes with the PIT probably derived from very labile soil carbon depletion, as shown in the simulations. This was not, however, confirmed by soil carbon measurements, which leaves open the possibility of adaptation within the microbial community.     

The FSHD2 Gene SMCHD1 Is a Modifier of Disease Severity in Families Affected by FSHD1

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4 to a size of 1–10 units. The residual number of D4Z4 units inversely correlates with clinical severity, but significant clinical variability exists. Each unit contains a copy of the DUX4 retrogene. Repeat contractions are associated with changes in D4Z4 chromatin structure that increase the likelihood of DUX4 expression in skeletal muscle, but only when the repeat resides in a genetic background that contains a DUX4 polyadenylation signal. Mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier of D4Z4, also result in the increased likelihood of DUX4 expression in individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may act as a genetic modifier in FSHD1. We describe three unrelated individuals with FSHD1 presenting an unusual high clinical severity based on their upper-sized FSHD1 repeat array of nine units. Each of these individuals also carries a mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which the FSHD2 gene can act as modifier for disease severity in families affected by FSHD1.     

Relationship between Obesity and Massive Transfusion Needs in Trauma Patients,and Validation of TASH Score in Obese Population: A Retrospective Study on 910 Trauma Patients

Background

Prediction of massive transfusion (MT) is challenging in management of trauma patients. However, MT and its prediction were poorly studied in obese patients. The main objective was to assess the relationship between obesity and MT needs in trauma patients. The secondary objectives were to validate the Trauma Associated Severe Hemorrhage (TASH) score in predicting MT in obese patients and to use a grey zone approach to optimize its ability to predict MT.

Methods and Findings

An observational retrospective study was conducted in a Level I Regional Trauma Center Trauma in obese and non-obese patients. MT was defined as ≥10U of packed red blood cells in the first 24h and obesity as a BMI≥30kg/m². Between January 2008 and December 2012, 119 obese and 791 non-obese trauma patients were included. The rate of MT was 10% (94/910) in the whole population. The MT rate tended to be higher in obese patients than in non-obese patients: 15% (18/119, 95%CI 9‒23%) versus 10% (76/791, 95%CI 8‒12%), OR, 1.68 [95%CI 0.97‒2.92], p = 0.07. After adjusting for Injury Severity Score (ISS), obesity was significantly associated with MT rate (OR, 1.79[95%CI 1.00‒3.21], p = 0.049). The TASH score was higher in the obese group than in the non-obese group: 7(4–11) versus 5(2–10)(p<0.001). The area under the ROC curves of the TASH score in predicting MT was very high and comparable between the obese and non-obese groups: 0.93 (95%CI, 0.89‒0.98) and 0.94 (95%CI, 0.92‒0.96), respectively (p = 0.80). The grey zone ranged respectively from 10 to 13 and from 9 to 12 in obese and non obese patients, and allowed separating patients at low, intermediate or high risk of MT using the TASH score.

Conclusions

Obesity was associated with a higher rate of MT in trauma patients. The predictive performance of the TASH score and the grey zones were robust and comparable between obese and non-obese patients.     

Biological Status and Dietary Intakes of Iron,Zinc and Vitamin A among Women and Preschool Children in Rural Burkina Faso

Background

Food-based approaches such as biofortification are meant to sustainably address micronutrient deficiencies in poor settings. Knowing more about micronutrient intakes and deficiencies is a prerequisite to designing and evaluating interventions.

Objective

The objectives of the study were to assess biological status and dietary intakes of iron, zinc and vitamin A among women and children aged 36–59 months in rural Burkina Faso and to study relationships between intake and status to better inform future food-based interventions.

Design

A cross-sectional survey was carried out in two rural provinces of Burkina Faso on a random cluster sample of 480 mother-child pairs. Dietary data was obtained by 24-hour recalls repeated on a random sub-selection of 37.5% of subjects to allow calculation of nutrient’s probability of adequacy (PA). Biomarkers were measured on a sub-sample of 180 mother-child pairs. Blood samples were analyzed for hemoglobin, serum ferritin, soluble transferrin receptors (sTfR), C-reactive protein, alpha-1-glycoprotein, serum zinc concentration (SZnC) and retinol. For each micronutrient the relationship between biomarker and dietary intake was investigated by multiple linear regression models accounting for inflammatory biomarkers.

Results

Mean PA for iron, zinc and vitamin A was 0.49, 0.87 and 0.21 among women and 0.61, 0.95 and 0.33 among children, respectively. Prevalence of anemia, corrected low serum ferritin and high sTfR was 37.6%, 4.0% and 77.5% among women and 72.1%, 1.5% and 87.6% among children, respectively. Prevalence of low SZnC and corrected low serum retinol was 39.4% and 12.0% among women and 63.7% and 24.8% among children, respectively. There was a tendency for a positive relationship between vitamin A intakes and serum retinol among women (β = 0.0003, P = 0.06). Otherwise, no link was found between micronutrients biomarkers and intakes.

Conclusion

Our study depicted different images of micronutrient deficiencies when based on dietary intakes or biomarkers results, thus highlighting the need for more suitable biomarkers and more precise measures of absorbable micronutrient intakes at the individual level. It thus points to challenges in the design and evaluation of future biofortification or other food-based interventions in rural areas of Burkina Faso.     

A New Combination with D-Cateslytin to Eradicate Root Canal Pathogens

International Journal of Peptide Research and Therapeutics - The success of endodontic treatments depends on the elimination of intracanal pathogens. Since irrigation and instrumentation can only...