The Role of Microglia in Bacterial Meningitis: Inflammatory Response, Experimental Models and New Neuroprotective Therapeutic Strategies

Microglia have a pivotal role in the pathophysiology of bacterial meningitis. The goal of this review is to provide an overview on how microglia respond to bacterial pathogens targeting the brain, how the interplay between microglia and bacteria can be studied experimentally, and possible ways to use gained knowledge to identify novel preventive and therapeutic strategies. We discuss the dual role of microglia in disease development, the beneficial functions crucial for bacterial clearing, and the destructive properties through triggering neuroinflammation, characterized by cytokine and chemokine release which leads to leukocyte trafficking through the brain vascular endothelium and breakdown of the blood-brain barrier integrity. Due to intrinsic complexity of microglia and up until recently lack of specific markers, the study of microglial response to bacterial pathogens is challenging. New experimental models and techniques open up possibilities to accelerate progress in the field. We review existing models and discuss possibilities and limitations. Finally, we summarize recent findings where bacterial virulence factors are identified to be important for the microglial response, and how manipulation of evoked responses could be used for therapeutic or preventive purposes. Among promising approaches are: modulations of microglia phenotype switching toward anti-inflammatory and phagocytic functions, the use of non-bacterolytic antimicrobials, preventing release of bacterial components into the neural milieu and consequential amplification of immune activation, and protection of the blood-brain barrier integrity

The Proteasome-Ubiquitin System Is Required for Efficient Killing of Intracellular Streptococcus pneumoniae by Brain Endothelial Cells

Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium that causes serious invasive diseases, such as pneumonia, bacteremia, and meningitis, with high morbidity and mortality throughout the world. Before causing invasive disease, S. pneumoniae encounters cellular barriers, which are often composed of endothelial cells, like the alveolar-capillary barrier and the blood-brain barrier. S. pneumoniae adheres to endothelial cells and may invade them, which requires an efficient host response to the intracellular bacteria. The precise intracellular fate of S. pneumoniae during infection still remains a subject of debate. The proteasome-ubiquitin system is largely responsible for the degradation of misfolded, damaged, or no-longeruseful proteins. Recently, the role of the proteasome-ubiquitin system in the clearing of invading bacteria and viruses has been more closely studied. In this study, we show that inhibition of the proteasome-ubiquitin system leads to a marked increase in S. pneumoniae survival inside host cells. Immunofluorescence analysis showed that intracellular pneumococci colocalized with proteasome and ubiquitin in human endothelial cells in vitro. Confocal imaging analysis demonstrated that in the brains of mice intravenously infected with S. pneumoniae, the bacteria were inside endothelial cells, where they colocalized with proteasome and ubiquitin signals. In conclusion, our data indicate that a fully functional proteasome-ubiquitin system in endothelial cells is crucial for efficient killing of intracellular S. pneumoniae. IMPORTANCE Bacterial meningitis is a serious invasive disease with high morbidity and mortality. How bacteria traverse the blood-brain barrier in vivo and what mechanisms are employed by the host to prevent invasion are still unclear. Our data show that inhibition of the proteasome-ubiquitin system in vitro leads to a significant increase in S. pneumoniae survival inside brain endothelial cells. Confocal imaging analysis of brain tissue from mice intravenously infected with pneumococci demonstrated that the bacteria are inside brain microvascular endothelial cells, where they associate with the proteasome and ubiquitin. This is, as far as we know, the first report that demonstrates that Streptococcus pneumoniae invades endothelial cells of the bloodbrain barrier in vivo. The host requires the proteasome-ubiquitin system for an efficient decimation of intracellular S. pneumoniae

Streptococcus pneumoniae Interacts with pIgR Expressed by the Brain Microvascular Endothelium but Does Not Co-Localize with PAF Receptor

Streptococcus pneumoniae is thought to adhere to the blood-brain barrier (BBB) endothelium prior to causing meningitis. The platelet activating factor receptor (PAFR) has been implicated in this adhesion but there is a paucity of data demonstrating direct binding of the bacteria to PAFR. Additionally, studies that inhibit PAFR strongly suggest that alternative receptors for pneumococci are present on the endothelium. Therefore, we studied the roles of PAFR and pIgR, an established epithelial pneumococcal receptor, in pneumococcal adhesion to brain endothelial cells in vivo. Mice were intravenously infected with pneumococci and sacrificed at various time points before meningitis onset. Co-localization of bacteria with PAFR and pIgR was investigated using immunofluorescent analysis of the brain tissue. In vitro blocking with antibodies and incubation of pneumococci with endothelial cell lysates were used to further probe bacteria-receptor interaction. In vivo as well as in vitro pneumococci did not co-localize with PAFR. On the other hand the majority of S. pneumoniae co-localized with endothelial pIgR and pIgR blocking reduced pneumococcal adhesion to endothelial cells. Pneumococci physically interacted with pIgR in endothelial cell lysates. In conclusion, bacteria did not associate with PAFR, indicating an indirect role of PAFR in pneumococcal adhesion to endothelial cells. In contrast, pIgR on the BBB endothelium may represent a novel pneumococcal adhesion receptor

A relocatable ocean modelling platform for downscaling to shelf-coastal areas to support disaster risk reduction

High-impact ocean weather events and climate extremes can have devastating effects on coastal zones and small islands. Marine Disaster Risk Reduction (DRR) is a systematic approach to such events, through which the risk of disaster can be identified, assessed and reduced. This can be done by improving ocean and atmosphere prediction models, data assimilation for better initial conditions and developing an efficient and sustainable impact forecasting methodology for Early Warnings Systems. A common user request during disaster remediation actions is for high-resolution information, which can be derived from easily deployable numerical models nested into operational larger-scale ocean models. The Structured and Unstructured Relocatable Ocean Model for Forecasting (SURF) enables users to rapidly deploy a nested high-resolution numerical model into larger-scale ocean forecasts. Rapidly downscaling the currents, sea level, temperature, and salinity fields is critical in supporting emergency responses to extreme events and natural hazards in the world’s oceans. The most important requirement in a relocatable model is to ensure that the interpolation of low-resolution ocean model fields (analyses and reanalyses) and atmospheric forcing is tested for different model domains. The provision of continuous ocean circulation forecasts through the Copernicus Marine Environment Monitoring Service (CMEMS) enables this testing. High-resolution SURF ocean circulation forecasts can be provided to specific application models such as oil spill fate and transport models, search and rescue trajectory models, and ship routing models requiring knowledge of meteooceanographic conditions. SURF was used to downscale CMEMS circulation analyses in four world ocean regions, and the high-resolution currents it can simulate for specific applications are examined. The SURF downscaled circulation fields show that the marine current resolutions affect the quality of the application models to be used for assessing disaster risks, particularly near coastal areas where the coastline geometry must be resolved through a numerical grid, and high-frequency coastal currents must be accurately simulated

Impacts of thinning of a Mediterranean oak forest on soil properties influencing water infiltration

In Mediterranean ecosystems, special attention needs to be paid to forest-water relationships due to water scarcity. In this context, Adaptive Forest Management (AFM) has the objective to establish how forest resources have to be managed with regards to the efficient use of water, which needs maintaining healthy soil properties even after disturbance. The main objective of this investigation was to understand the effect of one of the AFM methods, namely forest thinning, on soil hydraulic properties. At this aim, soil hydraulic characterization was performed on two contiguous Mediterranean oak forest plots, one of them thinned to reduce the forest density from 861 to 414 tree per ha. Three years after the intervention, thinning had not affected soil water permeability of the studied plots. Both ponding and tension infiltration runs yielded not significantly different saturated, Ks, and unsaturated, K-20, hydraulic conductivity values at the thinned and control plots. Therefore, thinning had no an adverse effect on vertical water fluxes at the soil surface. Mean Ks values estimated with the ponded ring infiltrometer were two orders of magnitude higher than K-20 values estimated with the minidisk infiltrometer, revealing probably soil structure with macropores and fractures . The input of hydrophobic organic matter, as a consequence of the addition of plant residues after the thinning treatment, resulted in slight differences in terms of both water drop penetration time, WDPT, and the index of water repellency, R, between thinned and control plots. Soil water repellency only affected unsaturated soil hydraulic conductivity measurements. Moreover, K-20 values showed a negative correlation with both WDPT and R, whereas Ks values did not, revealing that the soil hydrophobic behavior has no impact on saturated hydraulic conductivity

The VIMOS Public Extragalactic Redshift Survey (VIPERS) : The decline of cosmic star formation: quenching, mass, and environment connections

RT acknowledges financial support from the European Research Council through grant n. 202686.We use the final data of the VIMOS Public Extragalactic Redshift Survey (VIPERS) to investigate the effect of the environment on the evolution of galaxies between z = 0.5 and z = 0.9. We characterise local environment in terms of the density contrast smoothed over a cylindrical kernel, the scale of which is defined by the distance to the fifth nearest neighbour. This is performed by using a volume-limited sub-sample of galaxies complete up to z = 0.9, but allows us to attach a value of local density to all galaxies in the full VIPERS magnitude-limited sample to i < 22.5. We use this information to estimate how the distribution of galaxy stellar masses depends on environment. More massive galaxies tend to reside in higher-density environments over the full redshift range explored. Defining star-forming and passive galaxies through their (NUV-r) vs. (r-K) colours, we then quantify the fraction of star-forming over passive galaxies, fap, as a function of environment at fixed stellar mass. fap is higher in low-density regions for galaxies with masses ranging from log (M/M⊙) = 10.38 (the lowest value explored) to at least log (M/M⊙) ~ 11.3, although with decreasing significance going from lower to higher masses. This is the first time that environmental effects on high-mass galaxies are clearly detected at redshifts as high as z ~ 0.9. We compared these results to VIPERS-like galaxy mock catalogues based on a widely used galaxy formation model. The model correctly reproduces fap in low-density environments, but underpredicts it at high densities. The discrepancy is particularly strong for the lowest-mass bins. We find that this discrepancy is driven by an excess of low-mass passive satellite galaxies in the model. In high-density regions, we obtain a better (although not perfect) agreement of the model fap with observations by studying the accretion history of these model galaxies (that is, the times when they become satellites), by assuming either that a non-negligible fraction of satellites is destroyed, or that their quenching timescale is longer than ~ 2 Gyr.PostprintPeer reviewe

The VIMOS Public Extragalactic Redshift Survey (VIPERS). Downsizing of the blue cloud and the influence of galaxy size on mass quenching over the last eight billion years

R.T. acknowledges financial support from the European Research Councilthrough grant No. 202686.We use the full VIPERS redshift survey in combination with SDSS-DR7 to explore the relationships between star-formation history (using d4000), stellar mass and galaxy structure, and how these relationships have evolved since z ~ 1. We trace the extents and evolutions of both the blue cloud and red sequence by fitting double Gaussians to the d4000 distribution of galaxies in narrow stellar mass bins, for four redshift intervals over 0 < z < 1. This reveals downsizing in star formation, since the high-mass limit of the blue cloud has retreated steadily from time from ℳ ~ 1011.2 M⊙ at z ~ 0.9 to ℳ ~ 1010.7 M⊙ to the present day. The number density of massive blue-cloud galaxies (ℳ ~ 1011 M⊙, d4000 < 1.55) drops sharply by a factor five between z ~ 0.8 and z ~ 0.5. These galaxies are becoming quiescent at a rate that largely matches  the increase in the numbers of massive passive galaxies seen over this period. We examine the size-mass relation of blue-cloud galaxies,  finding that its high-mass boundary runs along lines of constant ℳ /re or equivalently inferred velocity dispersion. Larger galaxies can continue to form stars to higher stellar masses than smaller galaxies. As  blue-cloud galaxies approach this high-mass limit, entering a narrow diagonal region within the size-mass plane termed the “quenching zone”, they start to be quenched, their d4000 values increasing to push them towards the green valley. In parallel, their structures change, showing higher Sérsic indices and central stellar mass densities. For these galaxies, bulge growth is required for them to reach the high-mass limit of the blue cloud and be quenched by internal mechanisms. The blue-cloud galaxies that are being quenched at z ~ 0.8 lie along the same size-mass relation as present day quiescent galaxies and seem the likely progenitors of today’s S0s.Publisher PDFPeer reviewe

Chronic constipation diagnosis and treatment evaluation: The "CHRO.CO.DI.T.E." study

Background: According to Rome criteria, chronic constipation (CC) includes functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C). Some patients do not meet these criteria (No Rome Constipation, NRC). The aim of the study was is to evaluate the various clinical presentation and management of FC, IBS-C and NRC in Italy. Methods: During a 2-month period, 52 Italian gastroenterologists recorded clinical data of FC, IBS-C and NRC patients, using Bristol scale, PAC-SYM and PAC-QoL questionnaires. In addition, gastroenterologists were also asked to record whether the patients were clinically assessed for CC for the first time or were in follow up. Diagnostic tests and prescribed therapies were also recorded. Results: Eight hundred seventy-eight consecutive CC patients (706 F) were enrolled (FC 62.5%, IBS-C 31.3%, NRC 6.2%). PAC-SYM and PAC-QoL scores were higher in IBS-C than in FC and NRC. 49.5% were at their first gastroenterological evaluation for CC. In 48.5% CC duration was longer than 10 years. A specialist consultation was requested in 31.6%, more frequently in IBS-C than in NRC. Digital rectal examination was performed in only 56.4%. Diagnostic tests were prescribed to 80.0%. Faecal calprotectin, thyroid tests, celiac serology, breath tests were more frequently suggested in IBS-C and anorectal manometry in FC. More than 90% had at least one treatment suggested on chronic constipation, most frequently dietary changes, macrogol and fibers. Antispasmodics and psychotherapy were more frequently prescribed in IBS-C, prucalopride and pelvic floor rehabilitation in FC. Conclusions: Patients with IBS-C reported more severe symptoms and worse quality of life than FC and NRC. Digital rectal examination was often not performed but at least one diagnostic test was prescribed to most patients. Colonoscopy and blood tests were the "first line" diagnostic tools. Macrogol was the most prescribed laxative, and prucalopride and pelvic floor rehabilitation represented a "second line" approach. Diagnostic tests and prescribed therapies increased by increasing CC severity

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p &lt; 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p &lt; 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p &lt; 0.0001) or urgent (20.4% vs. 38.5%; p &lt; 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p &lt; 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice