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Bacterial meningitis (BM) is a global public health issue that affects patients of all ages. The two leading causes of BM worldwide are Streptococcus pneumoniae (the pneumococcus) and Neisseria meningitidis (the meningococcus). Despite the use of antibiotics and vaccines, both pneumococcal meningitis (PM) and meningococcal meningitis (MM) result in high case fatality rates and long-term neurological sequelae. Moreover, increasing resistance to first-line antibiotics, limited vaccine coverage, serotype replacement in vaccinated population, and lack of adjunctive therapies to control brain damage are all matters of concern in the management of PM and MM. The availability of animal models of PM and MM is crucial to characterize the pathogenetic and pathophysiologic mechanisms of disease as well as to identify novel antimicrobial agents, adjuvant therapies and vaccine candidates. Historically, animal models of BM employed large animals to mimic the disease in humans, such as monkeys for MM and rabbits for PM. However, since the introduction of rodents, both rats and mice have demonstrated to be robust, reliable, and suitable species for modeling both PM and MM. Depending on the route of infection, the dose of bacterial inoculum, the animal age and strain, different experimental readouts are obtained that permit to answer specific scientific questions. This chapter describes the main features of two models of PM and MM developed in the infant rat and adult mouse, respectively. Each model system presents unique characteristics that allow to study different aspects of the disease. The broad range of different forms of brain injury that can be observed in the PM infant rat model enables to study the entire spectrum of the pathophysiology of brain damage in PM and allows to evaluate novel therapeutic strategies and their impact on long-term neurological sequelae. The MM mouse model is suitable to investigate the role of meningococcal virulence factors in the disease, the host–parasite interactions in the central nervous system, and the efficacy of drugs to control the infection and limit brain damage in MM.

BACKGROUND Treatment failure in pneumococcal meningitis due to antibiotic resistance is an increasing clinical challenge and alternatives to antibiotics warrant investigation. Phage-derived endolysins efficiently kill gram-positive bacteria including multi-drug resistant strains, making them attractive therapeutic candidates. The current study assessed the therapeutic potential of the novel endolysin PlyAZ3aT in an infant rat model of ceftriaxone-resistant pneumococcal meningitis. METHODS Efficacy of PlyAZ3aT was assessed in a randomized, blinded and controlled experimental study in infant Wistar rats. Meningitis was induced by intracisternal infection with 5 x 107 CFU/ml of a ceftriaxone-resistant clinical strain of S. pneumoniae, serotype 19A. Seventeen hours post infection (hpi), animals were randomized into 3 treatment groups and received either (i) placebo (phosphate buffered saline [PBS], n = 8), (ii) 50 mg/kg vancomycin (n = 10) or (iii) 400 mg/kg PlyAZ3aT (n = 8) via intraperitoneal injection. Treatments were repeated after 12 h. Survival at 42 hpi was the primary outcome; bacterial loads in cerebrospinal fluid (CSF) and blood were secondary outcomes. Additionally, pharmacokinetics of PlyAZ3aT in serum and CSF was assessed. RESULTS PlyAZ3aT did not improve survival compared to PBS, while survival for vancomycin treated animals was 70% which is a significant improvement when compared to PBS or PlyAZ3aT (p

Additional file 2: Figure S2. IL-1β significantly correlated with MMP-9 at 18 hpi (p=0.04, r=0.5126; n=17) (A), but showed only a trend at 42 hpi (p=0.07, r=0.3940; n=22) (B).

Swidden cultivation practices have been seen as a major driver of deforestation and forest degradation in Southeast Asia. Using two case studies from Vietnam, this paper examines discourses around swidden practices at multiple levels of governance. Our findings show diverse interpretations of swidden resulting in different policy preferences and policy translations when addressing the issue. At national level, swidden is blamed as a principal driver of deforestation and forest degradation, and as such is a practice to be eliminated. As a result of this national stance, provincial level authorities see the existence of swidden as a failure by which their political performance will be judged. Conversely, swidden communities are seen at district level as an innovative solution to help resource-limited police forces ensure national security in border areas. Local commune and village leaders view swidden as a traditional practice to be respected, so as to maintain harmonious relationships amongst social groups, and avoid ethnic groups protesting against the government. Such differences in discourses and political interests have led to swidden becoming an ‘invisible’ issue, with government authorities failing to collect and report on data. Not recognizing swidden also means that swidden actors are practically ‘forgotten’ in the design and implementation of Reducing Emissions from Deforestation and Forest Degradation (REDD+) and Payments for Ecosystem Services (PES). Their omission from forest conservation and management incentive programmes could lead to further social marginalization, and potentially result in deforestation and forest degradation in the area. Our findings suggest that REDD+ policies should take into account diverging political interests on controversial land uses such as swidden cultivation.

Payments for Ecosystem Services schemes, or PES, offer a useful approach to account for the largely unrecognized value of ecosystem services provided by the forestry sector. However, the actual impacts of PES schemes, both in effectively protecting the environmental quality of an ecosystem, such as the water filtration capacity of a forest, and on improving local livelihoods, often remain unknown. Policy evaluation in general, and for newly established policies in particular, plays a critical role in providing essential feedback about what is actually happening on the ground. Thus, for PES to generate outcomes that are effective, efficient and equitable, policy makers must develop a functional evaluation system. As PES schemes around the world face similar problems in monitoring and evaluation, we draw on the case of Vietnam—the first country in Asia to introduce a nationwide PES scheme—and analyze the effectiveness of the monitoring and evaluation activities of the Payment for Forest Environmental Services program (PFES). We also offer practical policy recommendations for future PFES implementation. We find that monitoring and evaluation of PFES in Vietnam is still in its infancy. Although there is a strong accounting of revenues generated from ecosystem services buyers, there is a discernible lack of ability to assess the quantity and quality of ecosystem services being enhanced by the program; fulfillment of contractual obligations; the appropriateness of financial flows; or socio-economic impacts of the program. We argue that a functioning PES evaluation system must include an accessible grievance mechanism to ensure transparency and accountability in the distribution of PES revenues from central to local levels.

Additional file 1: Figure S1. At 18 hpi, inflammatory cytokines – TNF-α, IL-6 and IL-1β – correlated with each other (n=17).

Pneumococcal meningitis (PM) causes damage to the hippocampus, a brain structure critically involved in learning and memory. Hippocampal injury-which compromises neurofunctional outcome-occurs as apoptosis of progenitor cells and immature neurons of the hippocampal dentate granule cell layer thereby impairing the regenerative capacity of the hippocampal stem cell niche. Repetitive transcranial magnetic stimulation (rTMS) harbours the potential to modulate the proliferative activity of this neuronal stem cell niche. In this study, specific rTMS protocols-namely continuous and intermittent theta burst stimulation (cTBS and iTBS)-were applied on infant rats microbiologically cured from PM by five days of antibiotic treatment. Following two days of exposure to TBS, differential gene expression was analysed by whole transcriptome analysis using RNAseq. cTBS provoked a prominent effect in inducing differential gene expression in the cortex and the hippocampus, whereas iTBS only affect gene expression in the cortex. TBS induced polarisation of microglia and astrocytes towards an inflammatory phenotype, while reducing neurogenesis, neuroplasticity and regeneration. cTBS was further found to induce the release of pro-inflammatory cytokines in vitro. We conclude that cTBS intensified neuroinflammation after PM, which translated into increased release of pro-inflammatory mediators thereby inhibiting neuroregeneration.

Additional file 1: Figure S1. At 18 hpi, inflammatory cytokines – TNF-α, IL-6 and IL-1β – correlated with each other (n=17).