Pharmacometabonomic characterization of xenobiotic and endogenous metabolic phenotypes that account for inter-individual variation in isoniazid-induced toxicological response

An NMR-based pharmacometabonomic approach was applied to investigate inter-animal variation in response to isoniazid (INH; 200 and 400 mg/kg) in male Sprague-Dawley rats, alongside complementary clinical chemistry and histopathological analysis. Marked inter-animal variability in central nervous system (CNS) toxicity was identified following administration of a high dose of INH, which enabled characterization of CNS responders and CNS non-responders. High-resolution post-dose urinary (1)H NMR spectra were modeled both by their xenobiotic and endogenous metabolic information sets, enabling simultaneous identification of the differential metabolic fate of INH and its associated endogenous metabolic consequences in CNS responders and CNS non-responders. A characteristic xenobiotic metabolic profile was observed for CNS responders, which revealed higher urinary levels of pyruvate isonicotinylhydrazone and β-glucosyl isonicotinylhydrazide and lower levels of acetylisoniazid compared to CNS non-responders. This suggested that the capacity for acetylation of INH was lower in CNS responders, leading to increased metabolism via conjugation with pyruvate and glucose. In addition, the endogenous metabolic profile of CNS responders revealed higher urinary levels of lactate and glucose, in comparison to CNS non-responders. Pharmacometabonomic analysis of the pre-dose (1)H NMR urinary spectra identified a metabolic signature that correlated with the development of INH-induced adverse CNS effects and may represent a means of predicting adverse events and acetylation capacity when challenged with high dose INH. Given the widespread use of INH for the treatment of tuberculosis, this pharmacometabonomic screening approach may have translational potential for patient stratification to minimize adverse events.

Migration, immobility and displacement outcomes following extreme events

There is growing international concern at the rise in the severity of impact and frequency of extreme environmental events, potentially as a manifestation of global environmental change. There is a widely held belief that this trend could be linked with a future rise in the migration or displacement of human populations. However, recent approaches to migration influenced by environmental change call into question the notion that migration can be ascribed in a singular way to particular environmental causes or events. This paper undertakes a systematic review of evidence on population movements associated with weather-related extreme events. The paper demonstrates that in the face of extreme environmental events, it is important to distinguish between three outcomes – migration, displacement, and immobility – each of which interact and respond to multiple drivers. It also proposes a further insight: that both those who move, and those who do not move, may find themselves trapped and vulnerable in the face of such extreme events. A review of evidence suggests that short-term displacement that goes hand-in-hand with loss of life, destruction of property and economic disruption poses significant risks not because it is ‘environmental migration’, but because it represents a failure of adaptation to environmental change.

Are the winters 2010 and 2012 archetypes exhibiting extreme opposite behavior of the North Atlantic jet stream?

The atmospheric circulation over the North Atlantic-European sector experienced exceptional but highly contrasting conditions in the recent 2010 and 2012 winters (November-March; with the year dated by the relevant January). Evidence is given for the remarkably different locations of the eddy-driven westerly jet over the North Atlantic. In the 2010 winter the maximum of the jet stream was systematically between 30ºN and 40ºN (in the ‘south jet regime’), while in the 2012 winter it was predominantly located around 55ºN (north jet regime). These jet features underline the occurrence of either weak flow (2010) or strong and persistent ridges throughout the troposphere (2012). This is confirmed by the very different occurrence of blocking systems over the North Atlantic, associated with episodes of strong cyclonic (anticyclonic) Rossby wave breaking in 2010 (2012) winters. These dynamical features underlie strong precipitation and temperature anomalies over parts of Europe, with detrimental impacts on many socioeconomic sectors. Despite the highly contrasting atmospheric states, mid and high-latitude boundary conditions do not reveal strong differences in these two winters. The two winters were associated with opposite ENSO phases, but there is no causal evidence of a remote forcing from the Pacific sea surface temperatures. Finally, the exceptionality of the two winters is demonstrated in relation to the last 140 years. It is suggested that these winters may be seen as archetypes of North Atlantic jet variability under current climate conditions.

The 20 February 2010 Madeira flash-floods: synoptic analysis and extreme rainfall assessment

This study aims to characterise the rainfall exceptionality and the meteorological context of the 20 February 2010 flash-floods in Madeira (Portugal). Daily and hourly precipitation records from the available rain-gauge station networks are evaluated in order to reconstitute the temporal evolution of the rainstorm, as its geographic incidence, contributing to understand the flash-flood dynamics and the type and spatial distribution of the associated impacts. The exceptionality of the rainstorm is further confirmed by the return period associated with the daily precipitation registered at the two long-term record stations, with 146.9 mm observed in the city of Funchal and 333.8 mm on the mountain top, corresponding to an estimated return period of approximately 290 yr and 90 yr, respectively. Furthermore, the synoptic associated situation responsible for the flash-floods is analysed using different sources of information, e.g., weather charts, reanalysis data, Meteosat images and radiosounding data, with the focus on two main issues: (1) the dynamical conditions that promoted such anomalous humidity availability over the Madeira region on 20 February 2010 and (2) the uplift mechanism that induced deep convection activity.

Factors contributing to the development of extreme North Atlantic cyclones and their relationship with the NAO

The occurrence of extreme cyclones is analysed in terms of their relationship to the NAO phase and the dominating environmental variables controlling their intensification. These are latent energy (equivalent potential temperature 850 hPa is used as an indicator), upper-air baroclinicity, horizontal divergence and jet stream strength. Cyclones over the North Atlantic are identified and tracked using a numerical algorithm, permitting a detailed analysis of their life cycles. Extreme cyclones are selected as the 10% most severe in terms of intensity. Investigations focus on the main strengthening phase of each cyclone. The environmental factors are related to the NAO, which affects the location and orientation of the cyclone tracks, thus explaining why extreme cyclones occur more (less) frequently during strong positive (negative) NAO phases. The enhanced number of extreme cyclones in positive NAO phases can be explained by the larger area with suitable growth conditions, which is better aligned with the cyclone tracks and is associated with increased cyclone life time and intensity. Moreover, strong intensification of cyclones is frequently linked to the occurrence of extreme values of growth factors in the immediate vicinity of the cyclone centre. Similar results are found for ECHAM5/OM1 for present day conditions, demonstrating that relationships between the environment factors and cyclones are also valid in the GCM. For future climate conditions (following the SRES A1B scenario), the results are similar, but a small increase of the frequency of extreme values is detected near the cyclone cores. On the other hand, total cyclone numbers decrease by 10% over the North Atlantic. An exception is the region near the British Isles, which features increased track density and intensity of extreme cyclones irrespective of the NAO phase. These changes are associated with an intensified jet stream close to Europe. Moreover, an enhanced frequency of explosive developments over the British Isles is found, leading to more frequent windstorms affecting Europe.

Extreme wind storms over Europe in present and future climate: a cluster analysis approach

Boreal winter wind storm situations over Central Europe are investigated by means of an objective cluster analysis. Surface data from the NCEP-Reanalysis and ECHAM4/OPYC3-climate change GHG simulation (IS92a) are considered. To achieve an optimum separation of clusters of extreme storm conditions, 55 clusters of weather patterns are differentiated. To reduce the computational effort, a PCA is initially performed, leading to a data reduction of about 98 %. The clustering itself was computed on 3-day periods constructed with the first six PCs using "k-means" clustering algorithm. The applied method enables an evaluation of the time evolution of the synoptic developments. The climate change signal is constructed by a projection of the GCM simulation on the EOFs attained from the NCEP-Reanalysis. Consequently, the same clusters are obtained and frequency distributions can be compared. For Central Europe, four primary storm clusters are identified. These clusters feature almost 72 % of the historical extreme storms events and add only to 5 % of the total relative frequency. Moreover, they show a statistically significant signature in the associated wind fields over Europe. An increased frequency of Central European storm clusters is detected with enhanced GHG conditions, associated with an enhancement of the pressure gradient over Central Europe. Consequently, more intense wind events over Central Europe are expected. The presented algorithm will be highly valuable for the analysis of huge data amounts as is required for e.g. multi-model ensemble analysis, particularly because of the enormous data reduction.

Synoptic preconditions for extreme flooding during the summer Asian Monsoon in the Mumbai area

The summer monsoon season is an important hydrometeorological feature of the Indian subcontinent and it has significant socioeconomic impacts. This study is aimed at understanding the processes associated with the occurrence of catastrophic flood events. The study has two novel features that add to the existing body of knowledge about the South Asian Monsoon: 1) combine traditional hydrometeorological observations (rain gauge measurements) with unconventional data (media and state historical records of reported flooding) to produce value-added century-long time-series of potential flood events, and 2) identify the larger regional synoptic conditions leading to days with flood potential in the time-series. The promise of mining unconventional data to extend hydrometeorological records is demonstrated in this study. The synoptic evolution of flooding events in the western-central coast of India and the densely populated Mumbai area are shown to correspond to active monsoon periods with embedded low-pressure centers and have far upstream influence from the western edge of the Indian Ocean basin. The coastal processes along the Arabian Peninsula where the currents interact with the continental shelf are found to be key features of extremes during the South Asian Monsoon

The extreme European summer 2012

The European summer of 2012 was marked by strongly contrasting rainfall anomalies, which led to flooding in northern Europe and droughts and wildfires in southern Europe. This season was not an isolated event, rather the latest in a string of summers characterized by a southward shifted Atlantic storm track as described by the negative phase of the SNAO. The degree of decadal variability in these features suggests a role for forcing from outside the dynamical atmosphere, and preliminary numerical experiments suggest that the global SST and low Arctic sea ice extent anomalies are likely to have played a role and that warm North Atlantic SSTs were a particular contributing factor. The direct effects of changes in radiative forcing from greenhouse gas and aerosol forcing are not included in these experiments, but both anthropogenic forcing and natural variability may have influenced the SST and sea ice changes.

Association between serotonin 5-HT-2C receptor gene (HTR2C) polymorphisms and obesity- and mental health-related phenotypes in a large population-based cohort

OBJECTIVE: Studies have shown that common single-nucleotide polymorphisms (SNPs) in the serotonin 5-HT-2C receptor (HTR2C) are associated with antipsychotic agent-induced weight gain and the development of behavioural and psychological symptoms. We aimed to analyse whether variation in the HTR2C is associated with obesity- and mental health-related phenotypes in a large population-based cohort. METHOD: Six tagSNPs, which capture all common genetic variation in the HTR2C gene, were genotyped in 4978 men and women from the European Prospective Investigation into Cancer (EPIC)-Norfolk study, an ongoing prospective population-based cohort study in the United Kingdom. To confirm borderline significant associations, the -759C/T SNP (rs3813929) was genotyped in the remaining 16 003 individuals from the EPIC-Norfolk study. We assessed social and psychological circumstances using the Health and Life Experiences Questionnaire. Genmod models were used to test associations between the SNPs and the outcomes. Logistic regression was performed to test for association of SNPs with obesity- and mental health- related phenotypes. RESULTS: Of the six HTR2C SNPs, only the T allele of the -759C/T SNP showed borderline significant associations with higher body mass index (BMI) (0.23 kg m(-2); (95% confidence interval (CI): 0.01-0.44); P=0.051) and increased risk of lifetime major depressive disorder (MDD) (Odds ratio (OR): 1.13 (95% CI: 1.01-1.22), P=0.02). The associations between the -759C/T and BMI and lifetime MDD were independent. As associations only achieved borderline significance, we aimed to validate our findings on the -759C/T SNP in the full EPIC-Norfolk cohort (n=20 981). Although the association with BMI remained borderline significant (beta=0.20 kg m(-2); 95% CI: 0.04-0.44, P=0.09), that with lifetime MDD (OR: 1.01; 95% CI: 0.94-1.09, P=0.73) was not replicated. CONCLUSIONS: Our findings suggest that common HTR2C gene variants are unlikely to have a major role in obesity- and mental health-related traits in the general population.

Contribution of land use changes to near-surface air temperatures during recent summer extreme heat events in the Phoenix Metropolitan Area

The impact of 1973–2005 land use–land cover (LULC) changes on near-surface air temperatures during four recent summer extreme heat events (EHEs) are investigated for the arid Phoenix, Arizona, metropolitan area using the Weather Research and Forecasting Model (WRF) in conjunction with the Noah Urban Canopy Model. WRF simulations were carried out for each EHE using LULC for the years 1973, 1985, 1998, and 2005. Comparison of measured near-surface air temperatures and wind speeds for 18 surface stations in the region show a good agreement between observed and simulated data for all simulation periods. The results indicate consistent significant contributions of urban development and accompanying LULC changes to extreme temperatures for the four EHEs. Simulations suggest new urban developments caused an intensification and expansion of the area experiencing extreme temperatures but mainly influenced nighttime temperatures with an increase of up to 10 K. Nighttime temperatures in the existing urban core showed changes of up to 2 K with the ongoing LULC changes. Daytime temperatures were not significantly affected where urban development replaced desert land (increase by 1 K); however, maximum temperatures increased by 2–4 K when irrigated agricultural land was converted to suburban development. According to the model simulations, urban landscaping irrigation contributed to cooling by 0.5–1 K in maximum daytime as well as minimum nighttime 2-m air temperatures in most parts of the urban region. Furthermore, urban development led to a reduction of the already relatively weak nighttime winds and therefore a reduction in advection of cooler air into the city.

Extreme bounds of democracy

What determines the emergence and survival of democracy? The authors apply extreme bounds analysis to test the robustness of fifty-nine factors proposed in the literature, evaluating over three million regressions with data from 165 countries from 1976 to 2002. The most robust determinants of the transition to democracy are gross domestic product (GDP) growth (a negative effect), past transitions (a positive effect), and Organisation for Economic Co-operation and Development membership (a positive effect). There is some evidence that fuel exporters and Muslim countries are less likely to see democracy emerge, although the latter finding is driven entirely by oil-producing Muslim countries. Regarding the survival of democracy, the most robust determinants are GDP per capita (a positive effect) and past transitions (a negative effect). There is some evidence that having a former military leader as the chief executive has a negative effect, while having other democracies as neighbors has a reinforcing effect.

Inflammatory modulation of exercise salience: using hormesis to return to a healthy lifestyle

Most of the human population in the western world has access to unlimited calories and leads an increasingly sedentary lifestyle. The propensity to undertake voluntary exercise or indulge in spontaneous physical exercise, which might be termed "exercise salience", is drawing increased scientific attention. Despite its genetic aspects, this complex behaviour is clearly modulated by the environment and influenced by physiological states. Inflammation is often overlooked as one of these conditions even though it is known to induce a state of reduced mobility. Chronic subclinical inflammation is associated with the metabolic syndrome; a largely lifestyle-induced disease which can lead to decreased exercise salience. The result is a vicious cycle that increases oxidative stress and reduces metabolic flexibility and perpetuates the disease state. In contrast, hormetic stimuli can induce an anti-inflammatory phenotype, thereby enhancing exercise salience, leading to greater biological fitness and improved functional longevity. One general consequence of hormesis is upregulation of mitochondrial function and resistance to oxidative stress. Examples of hormetic factors include calorie restriction, extreme environmental temperatures, physical activity and polyphenols. The hormetic modulation of inflammation, and thus, exercise salience, may help to explain the highly heterogeneous expression of voluntary exercise behaviour and therefore body composition phenotypes of humans living in similar obesogenic environments.