Signalling or binding: the role of the platelet‐activating factor receptor in invasive pneumococcal disease

Streptococcus pneumoniae (the pneumococcus) is an opportunistic human pathogen, which causes serious invasive disease such as pneumonia, bacteraemia and meningitis. The interaction of the bacteria with host receptors precedes the development of invasive disease. One host receptor implicated in pneumococcal adhesion to, invasion of and ultimately translocation of cell layers is the platelet‐activating factor receptor (PAFR). PAFR is a G‐protein coupled receptor which binds PAF, a potent phospholipid activator involved in many leucocyte functions, platelet aggregation and inflammation. PAFR has been proposed to bind S. pneumoniae and as such facilitate adhesion to, uptake by and transcytosis of endothelial cells leading to invasive disease. However, there is a shortage of biochemical data supporting direct interaction between PAFR and the bacteria, in addition to conflicting data on its role in development of invasive pneumococcal disease (IPD). In this review, we will discuss current literature on PAFR and S. pneumoniae and other pathogens,including data concerning human PAFR genetic variation related to IPD clinical aspects, to shed light on the importance of PAFR in IPD. Clarification of the role of this receptor in IPD development has the potential to enable the development of novel therapeutic strategies for treating pneumococcal disease by interfering with the PAFR.     

Post-stroke infection: A systematic review and meta-analysis

Background  

stroke is the main cause of disability in high-income countries, and ranks second as a cause of death worldwide. Patients with acute stroke are at risk for infections, but reported post-stroke infection rates vary considerably. We performed a systematic review and meta-analysis to estimate the pooled post-stroke infection rate and its effect on outcome.     

Weight-Bearing and Mobilization in the Postoperative Care of Ankle Fractures: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Cohort Studies

PurposeTo determine the effectiveness and safety of interventions used for rehabilitation after open reduction and internal fixation of ankle fractures.MethodsA systematic review and meta-analysis was performed using both randomized trials and cohort studies. The effect of mobilization, weight-bearing, and unprotected weight-bearing as tolerated on postoperative recovery was compared using the Olerud Molander score, return to work/daily activities, and the rate of complications.ResultsA total of 25 articles were included. Ankle exercises resulted in earlier return to work and/or daily activities compared to immobilization (mean difference (MD) -20.76 days; 95% confidence interval (CI) -40.02 to -1.50). There was no difference in the rate of complications between exercises and immobilization (risk ratio (RR) 1.22; 95% CI 0.60 to 2.45) or between early and late weight-bearing (RR 1.26; 95%CI 0.56 to 2.85).InterpretationResults of this meta-analysis show that following ankle surgery, 1) active exercises accelerate return to work and daily activities compared to immobilization, 2) early weight-bearing tends to accelerate return to work and daily activities compared to late weight-bearing. Active exercises in combination with immediate weight-bearing may be a safe option.     

Arbuscular mycorrhizal fungi associated with Artemisia umbelliformis Lam, an endangered aromatic species in Southern French Alps, influence plant P and essential oil contents

Root colonization by arbuscular mycorrhizal (AM) fungi of Artemisia umbelliformis, investigated in natural and cultivated sites in the Southern Alps of France, showed typical structures (arbuscules, vesicles, hyphae) as well as spores and mycelia in its rhizosphere. Several native AM fungi belonging to different Glomeromycota genera were identified as colonizers of A. umbelliformis roots, including Glomus tenue, Glomus intraradices, G. claroideum/etunicatum and a new Acaulospora species. The use of the highly mycorrhizal species Trifolium pratense as a companion plant impacted positively on mycorrhizal colonization of A. umbelliformis under greenhouse conditions. The symbiotic performance of an alpine microbial community including native AM fungi used as inoculum on A. umbelliformis was evaluated in greenhouse conditions by comparison with mycorrhizal responses of two other alpine Artemisia species, Artemisia glacialis and Artemisia genipi Weber. Contrary to A. genipi Weber, both A. umbelliformis and A. glacialis showed a significant increase of P concentration in shoots. Volatile components were analyzed by GC–MS in shoots of A. umbelliformis 6 months after inoculation. The alpine microbial inoculum increased significantly the percentage of E-β-ocimene and reduced those of E-2-decenal and (E,E)-2-4-decadienal indicating an influence of alpine microbial inoculum on essential oil production. This work provides practical indications for the use of native AM fungi for A. umbelliformis field culture.     

Meningococcal Factor H Binding Protein fHbpd184 Polymorphism Influences Clinical Course of Meningococcal Meningitis

Factor H Binding protein (fHbp) is an important meningococcal virulence factor, enabling the meningococcus to evade the complement system, and a main target for vaccination. Recently, the structure of fHBP complexed with factor H (fH) was published. Two fHbp glutamic acids, E₂₈₃ and E₃₀₄, form salt bridges with fH, influencing interaction between fHbp and fH. Fifteen amino acids were identified forming hydrogen bonds with fH. We sequenced fHbp of 254 meningococcal isolates from adults with meningococcal meningitis included in a prospective clinical cohort to study the effect of fHbp variants on meningococcal disease severity and outcome. All fHbp of subfamily A had E304 substituted with T304. Of the 15 amino acids in fHbp making hydrogen bonds to fH, 3 were conserved, 11 show a similar distribution between the two fHbp subfamilies as the polymorphism at position 304. The proportion of patients infected with meningococci with fHbp of subfamily A with unfavorable outcome was 2.5-fold lower than that of patients infected with meningococci with fHbp of subfamily B (2 of 40 (5%) vs. 27 of 213 (13%) (P = 0.28). The charge of 2 of 15 amino acids (at position 184 and 306) forming hydrogen bonds was either basic or acidic. The affinity of fHbp_K184 and of fHbp_D184 for recombinant purified human fH was assessed by Surface Plasmon Resonance and showed average K_D of 2.60×10⁻⁸ and 1.74×10⁻⁸, respectively (ns). Patients infected with meningococci with fHbp_D184 were more likely to develop septic shock during admission (11 of 42 [26%] vs. 19 of 211 [9%]; P = 0.002) resulting in more frequent unfavorable outcome (9 of 42 [21%] vs. 20 of 211 [10%]; P = 0.026). In conclusion, we dentified fHBP_D184 to be associated with septic shock in patients with meningococcal meningitis.     

The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo

The β-site amyloid precursor protein-cleaving enzyme BACE1 is a prime drug target for Alzheimer disease. However, the function and the physiological substrates of BACE1 remain largely unknown. In this work, we took a quantitative proteomic approach to analyze the secretome of primary neurons after acute BACE1 inhibition, and we identified several novel substrate candidates for BACE1. Many of these molecules are involved in neuronal network formation in the developing nervous system. We selected the adhesion molecules L1 and CHL1, which are crucial for axonal guidance and maintenance of neural circuits, for further validation as BACE1 substrates. Using both genetic BACE1 knock-out and acute pharmacological BACE1 inhibition in mice and cell cultures, we show that L1 and CHL1 are cleaved by BACE1 under physiological conditions. The BACE1 cleavage sites at the membrane-proximal regions of L1 (between Tyr(1086) and Glu(1087)) and CHL1 (between Gln(1061) and Asp(1062)) were determined by mass spectrometry. This work provides molecular insights into the function and the pathways in which BACE1 is involved, and it will help to predict or interpret possible side effects of BACE1 inhibitor drugs in current clinical trials.     

Local and systemic mycorrhiza-induced protection against the ectoparasitic nematode Xiphinema index involves priming of defence gene responses in grapevine

The ectoparasitic dagger nematode (Xiphinema index), vector of Grapevine fanleaf virus (GFLV), provokes gall formation and can cause severe damage to the root system of grapevines. Mycorrhiza formation by Glomus (syn. Rhizophagus) intraradices BEG141 reduced both gall formation on roots of the grapevine rootstock SO4 (Vitis berlandieri×V. riparia) and nematode number in the surrounding soil. Suppressive effects increased with time and were greater when the nematode was post-inoculated rather than co-inoculated with the arbuscular mycorrhizal (AM) fungus. Using a split-root system, decreased X. index development was shown in mycorrhizal and non-mycorrhizal parts of mycorrhizal root systems, indicating that both local and systemic induced bioprotection mechanisms were active against the ectoparasitic nematode. Expression analyses of ESTs (expressed sequence tags) generated in an SSH (subtractive suppressive hybridization) library, representing plant genes up-regulated during mycorrhiza-induced control of X. index, and of described grapevine defence genes showed activation of chitinase 1b, pathogenesis-related 10, glutathione S-transferase, stilbene synthase 1, 5-enolpyruvyl shikimate-3-phosphate synthase, and a heat shock proein 70-interacting protein in association with the observed local and/or systemic induced bioprotection against the nematode. Overall, the data suggest priming of grapevine defence responses by the AM fungus and transmission of a plant-mediated signal to non-mycorrhizal tissues. Grapevine gene responses during AM-induced local and systemic bioprotection against X. index point to biological processes that are related either to direct effects on the nematode or to protection against nematode-imposed stress to maintain root tissue integrity.     

Costs and Cost-Effectiveness of Hypertension Screening and Treatment in Adults with Hypertension in Rural Nigeria in the Context of a Health Insurance Program

BackgroundHigh blood pressure is a leading risk factor for death and disability in sub-Saharan Africa (SSA). We evaluated the costs and cost-effectiveness of hypertension care provided within the Kwara State Health Insurance (KSHI) program in rural Nigeria.MethodsA Markov model was developed to assess the costs and cost-effectiveness of population-level hypertension screening and subsequent antihypertensive treatment for the population at-risk of cardiovascular disease (CVD) within the KSHI program. The primary outcome was the incremental cost per disability-adjusted life year (DALY) averted in the KSHI scenario compared to no access to hypertension care. We used setting-specific and empirically-collected data to inform the model. We defined two strategies to assess eligibility for antihypertensive treatment based on 1) presence of hypertension grade 1 and 10-year CVD risk of >20%, or grade 2 hypertension irrespective of 10-year CVD risk (hypertension and risk based strategy) and 2) presence of hypertension in combination with a CVD risk of >20% (risk based strategy). We generated 95% confidence intervals around the primary outcome through probabilistic sensitivity analysis. We conducted one-way sensitivity analyses across key model parameters and assessed the sensitivity of our results to the performance of the reference scenario.ResultsScreening and treatment for hypertension was potentially cost-effective but the results were sensitive to changes in underlying assumptions with a wide range of uncertainty. The incremental cost-effectiveness ratio for the first and second strategy respectively ranged from US$ 1,406 to US$ 7,815 and US$ 732 to US$ 2,959 per DALY averted, depending on the assumptions on risk reduction after treatment and compared to no access to antihypertensive treatment.ConclusionsHypertension care within a subsidized private health insurance program may be cost-effective in rural Nigeria and public-private partnerships such as the KSHI program may provide opportunities to finance CVD prevention care in SSA.