Pneumococcal meningitis causes accumulation of neurotoxic kynurenine metabolites in brain regions prone to injury

Pneumococcal meningitis (PM) is characterized by an intense inflammatory host reaction that contributes to the development of cortical necrosis and hippocampal apoptosis. Inflammatory conditions in the brain are known to induce tryptophan degradation along the kynurenine pathway, resulting in accumulation of neurotoxic metabolites. In the present study, we investigated the contribution of the kynurenine pathway to brain injury in experimental PM by measuring the concentration of its metabolites and the enzymatic activities and mRNA levels of its major enzymes in the vulnerable brain regions. In the late phase of acute PM, we found a significant transcriptional upregulation of kynurenine-3-hydroxylase and an accumulation of the neurotoxic metabolites 3-hydroxykynurenine (3-HKYN) and 3-hydroxyanthranilic acid in cortex and hippocampus. The positive correlation between the concentration of 3-HKYN and the extent of hippocampal apoptosis adds support to the concept that 3-HKYN contributes to brain injury in PM.

Climate change in mountain regions: how local communities adapt to extreme events

This paper examines how local communities adapt to climate change and how governance structures can foster or undermine adaptive capacity. Climate change policies, in general, and disaster risk management in mountain regions, in particular, are characterised by their multi-level and multi-sectoral nature during formulation and implementation. The involvement of numerous state and non-state actors at local to national levels produces a variety of networks of interaction and communication. The paper argues that the structure of these relational patterns is critical for understanding adaptive capacity. It thus proposes an expanded concept of adaptive capacity that incorporates (horizontal and vertical) actor integration and communication flow between these actors. The paper further advocates the use of formal social network analysis to assess these relational patterns. Preliminary results from research on adaptation to climate change in a Swiss mountain region vulnerable to floods and other natural hazards illustrate the conceptual and empirical significance of the main arguments.

Antibiotic use in adult outpatients in Switzerland in relation to regions, seasonality and point of care tests

The use of antibiotics is highest in primary care and directly associated with antibiotic resistance in the community. We assessed regional variations in antibiotic use in primary care in Switzerland and explored prescription patterns in relation to the use of point of care tests. Defined daily doses of antibiotics per 1000 inhabitants (DDD(1000pd) ) were calculated for the year 2007 from reimbursement data of the largest Swiss health insurer, based on the anatomic therapeutic chemical classification and the DDD methodology recommended by WHO. We present ecological associations by use of descriptive and regression analysis. We analysed data from 1 067 934 adults, representing 17.1% of the Swiss population. The rate of outpatient antibiotic prescriptions in the entire population was 8.5 DDD(1000pd) , and varied between 7.28 and 11.33 DDD(1000pd) for northwest Switzerland and the Lake Geneva region. DDD(1000pd) for the three most prescribed antibiotics were 2.90 for amoxicillin and amoxicillin-clavulanate, 1.77 for fluoroquinolones, and 1.34 for macrolides. Regions with higher DDD(1000pd) showed higher seasonal variability in antibiotic use and lower use of all point of care tests. In regression analysis for each class of antibiotics, the use of any point of care test was consistently associated with fewer antibiotic prescriptions. Prescription rates of primary care physicians showed variations between Swiss regions and were lower in northwest Switzerland and in physicians using point of care tests. Ecological studies are prone to bias and whether point of care tests reduce antibiotic use has to be investigated in pragmatic primary care trials.

Vulnerability to risk among small farmers in Tajikistan: results of a 2011 survey

Tajikistan is judged to be highly vulnerable to risk, including food insecurity risks and climate change risks. By some vulnerability measures it is the most vulnerable among all 28 countries in the World Bank’s Europe and Central Asia Region – ECA (World Bank 2009). The rural population, with its relatively high incidence of poverty, is particularly vulnerable. The Pilot Program for Climate Resilience (PPCR) in Tajikistan (2011) provided an opportunity to conduct a farm-level survey with the objective of assessing various dimensions of rural population’s vulnerability to risk and their perception of constraints to farming operations and livelihoods. The survey should be accordingly referred to as the 2011 PPCR survey. The rural population in Tajikistan is highly agrarian, with about 50% of family income deriving from agriculture (see Figure 4.1; also LSMS 2007 – own calculations). Tajikistan’s agriculture basically consists of two groups of producers: small household plots – the successors of Soviet “private agriculture” – and dehkan (or “peasant”) farms – new family farming structures that began to be created under relevant legislation passed after 1992 (Lerman and Sedik, 2008). The household plots manage 20% of arable land and produce 65% of gross agricultural output (GAO). Dehkan farms manage 65% of arable land and produce close to 30% of GAO. The remaining 15% of arable land is held in agricultural enterprises – the rapidly shrinking sector of corporate farms that succeeded the Soviet kolkhozes and sovkhozes and today produces less than 10% of GAO (TajStat 2011) The survey conducted in May 2011 focused on dehkan farms, as budgetary constraints precluded the inclusion of household plots. A total of 142 dehkan farms were surveyed in face-to-face interviews. They were sampled from 17 districts across all four regions – Sughd, Khatlon, RRP, and GBAO. The districts were selected so as to represent different agro-climatic zones, different vulnerability zones (based on the World Bank (2011) vulnerability assessment), and different food-insecurity zones (based on WFP/IPC assessments). Within each district, 3-4 jamoats were chosen at random and 2-3 farms were selected in each jamoat from lists provided by jamoat administration so as to maximize the variability by farm characteristics. The sample design by region/district is presented in Table A, which also shows the agro-climatic zone and the food security phase for each district. The sample districts are superimposed on a map of food security phases based on IPC April 2011.

[Bullet and shrapnel injuries in the face and neck regions. Current aspects of wound ballistics]

A basic understanding of the ballistic behaviour of projectiles or fragments after entering the human body is essential for the head and neck surgeon in the military environment in order to anticipate the diagnostic and therapeutic consequences of this type of injury. Although a large number of factors influence the missile in flight and after penetration of the body, the most important factor is the amount of energy transmitted to the tissue. Long guns (rifles or shotguns) have a much higher muzzle energy compared to handguns, explaining why the remote effects beyond the bullet track play a major role. While most full metal jacket bullets release their energy after 12-20 cm (depending on the calibre), soft point bullets release their energy immediately after entry into the human body. This results in a major difference in extremity wounds, but not so much in injuries with long bullet paths (e.g. diagonal shots). Shrapnel wounds are usually produced with similarly high kinetic energy to those caused by hand- and long guns. However, fragments tend to dissipate the entire amount of energy within the body, which increases the degree of tissue disruption. Of all relevant injuries in the head and neck region, soft tissue injuries make up the largest proportion (60%), while injuries to the face are seen three times more often than injuries to the neck. Concomitant intracranial or spinal injury is seen in 30% of cases. Due to high levels of wound contamination, the infection rate is approximately 15%, often associated with a complicated and/or multiresistant spectrum of germs.

Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease.