The Glymphatic System: a Potential Key Player in Bacterial Meningitis

The glial-lymphatic system (glymphatic system) is a recently characterized fluid clearance pathway of the central nervous system. Glymphatic system disfunctions leading to defects in drainage of the cerebrospinal fluid have been associated with several neurological disorders. In their article, J. S. Generoso, S. Thorsdottir, A. Collodel, R. R. E. Santo, et al. (mBio 13:e01886-22, 2022, https://doi.org/10.1128/mBio.01886-22) have now associated impaired glymphatic system functionality to neurological sequelae of murine meningitis caused by Streptococcus pneumoniae. Their work provides an initial and important step into the systematic evaluation of a potential impact of glymphatic system functionality on disease severity and sequelae in meningitis

Streamlined islands and the English Channel megaflood hypothesis

Recognising ice-age catastrophic megafloods is important because they had significant impact on large-scale drainage evolution and patterns of water and sediment movement to the oceans, and likely induced very rapid, short-term effects on climate. It has been previously proposed that a drainage system on the floor of the English Channel was initiated by catastrophic flooding in the Pleistocene but this suggestion has remained controversial. Here we examine this hypothesis through an analysis of key landform features. We use a new compilation of multi- and single-beam bathymetry together with sub-bottom profiler data to establish the internal structure, planform geometry and hence origin of a set of 36 mid-channel islands. Whilst there is evidence of modern-day surficial sediment processes, the majority of the islands can be clearly demonstrated to be formed of bedrock, and are hence erosional remnants rather than depositional features. The islands display classic lemniscate or tear-drop outlines, with elongated tips pointing downstream, typical of streamlined islands formed during high-magnitude water flow. The length-to-width ratio for the entire island population is 3.4 ± 1.3 and the degree-of-elongation or k-value is 3.7 ± 1.4. These values are comparable to streamlined islands in other proven Pleistocene catastrophic flood terrains and are distinctly different to values found in modern-day rivers. The island geometries show a correlation with bedrock type: with those carved from Upper Cretaceous chalk having larger length-to-width ratios (3.2 ± 1.3) than those carved into more mixed Paleogene terrigenous sandstones, siltstones and mudstones (3.0 ± 1.5). We attribute these differences to the former rock unit having a lower skin friction which allowed longer island growth to achieve minimum drag. The Paleogene islands, although less numerous than the Chalk islands, also assume more perfect lemniscate shapes. These lithologies therefore reached island equilibrium shape more quickly but were also susceptible to total erosion. Our observations support the hypothesis that the islands were initially carved by high-water volume flows via a unique catastrophic drainage of a pro-glacial lake in the southern North Sea at the Dover Strait rather than by fluvial erosion throughout the Pleistocene

Synergistic activity of mobile genetic element defences in Streptococcus pneumoniae

A diverse set of mobile genetic elements (MGEs) transmit between Streptococcus pneumoniae cells, but many isolates remain uninfected. The best-characterised defences against horizontal transmission of MGEs are restriction-modification systems (RMSs), of which there are two phase-variable examples in S. pneumoniae. Additionally, the transformation machinery has been proposed to limit vertical transmission of chromosomally integrated MGEs. This work describes how these mechanisms can act in concert. Experimental data demonstrate RMS phase variation occurs at a sub-maximal rate. Simulations suggest this may be optimal if MGEs are sometimes vertically inherited, as it reduces the probability that an infected cell will switch between RMS variants while the MGE is invading the population, and thereby undermine the restriction barrier. Such vertically inherited MGEs can be deleted by transformation. The lack of between-strain transformation hotspots at known prophage att sites suggests transformation cannot remove an MGE from a strain in which it is fixed. However, simulations confirmed that transformation was nevertheless effective at preventing the spread of MGEs into a previously uninfected cell population, if a recombination barrier existed between co-colonising strains. Further simulations combining these effects of phase variable RMSs and transformation found they synergistically inhibited MGEs spreading, through limiting both vertical and horizontal transmission

Selection and characterization of a promoter for expression of single-copy recombinant genes in Gram-positive bacteria

BACKGROUND: In the past ten years there has been a growing interest in engineering Gram-positive bacteria for biotechnological applications, including vaccine delivery and production of recombinant proteins. Usually, bacteria are manipulated using plasmid expression vectors. The major limitation of this approach is due to the fact that recombinant plasmids are often lost from the bacterial culture upon removal of antibiotic selection. We have developed a genetic system based on suicide vectors on conjugative transposons allowing stable integration of recombinant DNA into the chromosome of transformable and non-transformable Gram-positive bacteria. RESULTS: The aim of this work was to select a strong chromosomal promoter from Streptococcus gordonii to improve this genetic system making it suitable for expression of single-copy recombinant genes. To achieve this task, a promoterless gene encoding a chloramphenicol acetyltransferase (cat), was randomly integrated into the S. gordonii chromosome and transformants were selected for chloramphenicol resistance. Three out of eighteen chloramphenicol resistant transformants selected exhibited 100% stability of the phenotype and only one of them, GP215, carried the cat gene integrated as a single copy. A DNA fragment of 600 base pairs exhibiting promoter activity was isolated from GP215 and sequenced. The 5' end of its corresponding mRNA was determined by primer extention analysis and the putative -10 and a -35 regions were identified. To study the possibility of using this promoter (PP) for single copy heterologous gene expression, we created transcriptional fusions of PP with genes encoding surface recombinant proteins in a vector capable of integrating into the conjugative transposon Tn916. Surface recombinant proteins whose expression was controlled by the PP promoter were detected in Tn916-containing strains of S. gordonii and Bacillus subtilis after single copy chromosomal integration of the recombinant insertion vectors into the resident Tn916. The surface recombinant protein synthesized under the control of PP was also detected in Enterococcus faecalis after conjugal transfer of a recombinant Tn916 containing the transcriptional fusion. CONCLUSION: We isolated and characterized a S. gordonii chromosomal promoter. We demonstrated that this promoter can be used to direct expression of heterologous genes in different Gram-positive bacteria, when integrated in a single copy into the chromosome

Characteristics of drug-resistant tuberculosis in Abkhazia (Georgia), a high-prevalence area in Eastern Europe

Although multidrug-resistant (MDR) tuberculosis (TB) is a major public health problem in Eastern Europe, the factors contributing to emergence, spread and containment of MDR-TB are not well defined. Here, we analysed the characteristics of drug-resistant TB in a cross-sectional study in Abkhazia (Georgia) between 2003 and 2005, where standard short-course chemotherapy is supplemented with individualized drug-resistance therapy. Drug susceptibility testing (DST) and molecular typing were carried out for Mycobacterium tuberculosis complex strains from consecutive smear-positive TB patients. Out of 366 patients, 60.4% were resistant to any first-line drugs and 21% had MDR-TB. Overall, 25% of all strains belong to the Beijing genotype, which was found to be strongly associated with the risk of MDR-TB (OR 25.9, 95% CI 10.2-66.0) and transmission (OR 2.8, 95% CI 1.6-5.0). One dominant MDR Beijing clone represents 23% of all MDR-TB cases. The level of MDR-TB did not decline during the study period, coinciding with increasing levels of MDR Beijing strains among previously treated cases. Standard chemotherapy plus individualized drug-resistance therapy, guided by conventional DST, might be not sufficient to control MDR-TB in Eastern Europe in light of the spread of "highly transmissible" MDR Beijing strains circulating in the community

Treatment of tuberculosis in a region with high drug resistance: Outcomes, drug resistance amplification and re-infection

Introduction: Emerging antituberculosis drug resistance is a serious threat for tuberculosis (TB) control, especially in Eastern European countries. Methods: We combined drug susceptibility results and molecular strain typing data with treatment outcome reports to assess the influence of drug resistance on TB treatment outcomes in a prospective cohort of patients from Abkhazia (Georgia). Patients received individualized treatment regimens based on drug susceptibility testing (DST) results. Definitions for antituberculosis drug resistance and treatment outcomes were in line with current WHO recommendations. First and second line DST, and molecular typing were performed in a supranational laboratory for Mycobacterium tuberculosis (MTB) strains from consecutive sputum smear-positive TB patients at baseline and during treatment. Results: At baseline, MTB strains were fully drug-susceptible in 189/326 (58.0%) of patients. Resistance to at least H or R (PDR-TB) and multidrug-resistance (MDR-TB) were found in 69/326 (21.2%) and 68/326 (20.9%) of strains, respectively. Three MDR-TB strains were also extensively resistant (XDR-TB). During treatment, 3/189 (1.6%) fully susceptible patients at baseline were re-infected with a MDR-TB strain and 2/58 (3.4%) PDR-TB patients became MDR-TB due to resistance amplification. 5/ 47 (10.6%) MDR- patients became XDR-TB during treatment. Treatment success was observed in 161/189 (85.2%), 54/69 (78.3%) and 22/68 (32.3%) of patients with fully drug susceptible, PDR- and MDR-TB, respectively. Development of ofloxacin resistance was significantly associated with a negative treatment outcome. Conclusion: In Abkhazia, a region with high prevalence of drug resistant TB, the use of individualized MDR-TB treatment regimens resulted in poor treatment outcomes and XDR-TB amplification. Nosocomial transmission of MDR-TB emphasizes the importance of infection control in hospitals

Association between worldwide dietary and lifestyle patterns with total cholesterol concentrations and DALYs for infectious and cardiovascular diseases: An ecological analysis

Global dietary and lifestyle trends are primary risk factors for communicable and non-communicable diseases. An ecological analysis was conducted to examine the association of global dietary and lifestyle patterns with total cholesterol concentrations. This study also investigated whether total cholesterol modified the association between dietary and lifestyle habits with disability-adjusted-life-years-lost (DALYs) for infectious and cardiovascular diseases (CVDs). Country-specific mean total cholesterol concentrations and DALYs for infectious and CVDs were obtained. Data were then matched to country-specific food and energy availability for consumption and information on obesity, physical inactivity, urbanization, gross domestic product (GDP), life expectancy and smoking. Stepwise multiple regression models were developed to identify significant predictors of total cholesterol concentrations and DALYs for infectious and CVDs. Life expectancy and egg and meat consumption were significantly associated with cholesterol concentrations. DALYs for infectious diseases were associated with smoking, life expectancy and per capita GDP. Smoking was the only predictor of DALYs for CVDs. The improvement of socio-demographic conditions and economic growth is likely to reduce the burden of communicable diseases in developing countries. A concurring increase in non-communicable diseases is expected, and these results have, yet again, identified smoking as a primary risk factor for CVDs

Dietary nitrate does not modify blood pressure and cardiac output at rest and during exercise in older adults : a randomised cross over study

Dietary nitrate (〖NO〗_3^-) supplementation has been associated with improved vascular and metabolic health. We conducted a double-blind, cross-over, placebo-controlled RCT to investigate the effects of 7-day consumption of beetroot juice compared with placebo on 1) blood pressure (BP) measured in resting conditions and during exercise, 2) cardiac and peripheral vascular function and 3) biomarkers of inflammation, oxidative stress and endothelial integrity. Twenty non-smoking healthy participants aged 60-75y and BMI 20.0-29.9kg/m2 were recruited. Measurement were conducted before and after each 7-day intervention period. Consumption of 〖NO〗_3^- had no effect on resting systolic and diastolic BP. 〖NO〗_3^- consumption did not improve indexes of central and peripheral cardiac function responses during cardiopulmonary exercise testing. Dietary 〖NO〗_3^- supplementation did not modify biomarkers of inflammation, oxidative stress and endothelial integrity. This study do not support the short-term benefits of dietary 〖NO〗_3^- supplementation on physiological and biochemical markers of vascular health in older healthy adults. Trial Registration: ISRCTN1906495

Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis

Background: Approximately 7% of survivors from meningococcal meningitis (MM) suffer from neurological sequelae due to brain damage in the course of meningitis. The present study focuses on the role of matrix metalloproteinases (MMPs) in a novel mouse model of MM-induced brain damage. Methods: The model is based on intracisternal infection of BALB/c mice with a serogroup C Neisseria meningitidis strain. Mice were infected with meningococci and randomised for treatment with the MMP inhibitor batimastat (BB-94) or vehicle. Animal survival, brain injury and host-response biomarkers were assessed 48 h after meningococcal challenge. Results: Mice that received BB-94 presented significantly diminished MMP-9 levels (p < 0.01), intracerebral bleeding (p < 0.01), and blood brain barrier (BBB) breakdown (p < 0.05) in comparison with untreated animals. In mice suffering from MM, the amount of MMP- 9 measured by zymography significantly correlated with both intracerebral haemorrhage (p < 0.01) and BBB disruption (p < 0.05). Conclusions: MMPs significantly contribute to brain damage associated with experimental MM. Inhibition of MMPs reduces intracranial complications in mice suffering from MM, representing a potential adjuvant strategy in MM post-infection sequelae

Peripheral nervous system involvement in Parkinson's disease: Evidence and controversies

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