Timing of enteral feeding in cerebral malaria in resource-poor settings: a randomized trial

Background

Early start of enteral feeding is an established treatment strategy in intubated patients in intensive care since it reduces invasive bacterial infections and length of hospital stay. There is equipoise whether early enteral feeding is also beneficial in non-intubated patients with cerebral malaria in resource poor settings. We hypothesized that the risk of aspiration pneumonia might outweigh the potential benefits of earlier recovery and prevention of hypoglycaemia.

Method and Findings

A randomized trial of early (day of admission) versus late (after 60 hours in adults or 36 hours in children) start of enteral feeding was undertaken in patients with cerebral malaria in Chittagong, Bangladesh from May 2008 to August 2009. The primary outcome measures were incidence of aspiration pneumonia, hypoglycaemia and coma recovery time. The trial was terminated after inclusion of 56 patients because of a high incidence of aspiration pneumonia in the early feeding group (9/27 (33%)), compared to the late feeding group (0/29 (0%)), p = 0.001). One patient in the late feeding group, and none in the early group, had hypoglycaemia during admission. There was no significant difference in overall mortality (9/27 (33%) vs 6/29 (21%), p = 0.370), but mortality was 5/9 (56%) in patients with aspiration pneumonia.

Conclusions

In conclusion, early start of enteral feeding is detrimental in non-intubated patients with cerebral malaria in many resource-poor settings. Evidence gathered in resource rich settings is not necessarily transferable to resource-poor settings.

Trial Registration

Controlled-Trials.com ISRCTN57488577     

Serotonin and dopamine protect from hypothermia/rewarming damage through the CBS/H2S pathway

Biogenic amines have been demonstrated to protect cells from apoptotic cell death. Herein we show for the first time that serotonin and dopamine increase H(2)S production by the endogenous enzyme cystathionine-β-synthase (CBS) and protect cells against hypothermia/rewarming induced reactive oxygen species (ROS) formation and apoptosis. Treatment with both compounds doubled CBS expression through mammalian target of rapamycin (mTOR) and increased H(2)S production in cultured rat smooth muscle cells. In addition, serotonin and dopamine treatment significantly reduced ROS formation. The beneficial effect of both compounds was minimized by inhibition of their re-uptake and by pharmacological inhibition of CBS or its down-regulation by siRNA. Exogenous administration of H(2)S and activation of CBS by Prydoxal 5'-phosphate also protected cells from hypothermic damage. Finally, serotonin and dopamine pretreatment of rat lung, kidney, liver and heart prior to 24 h of hypothermia at 3°C followed by 30 min of rewarming at 37°C upregulated the expression of CBS, strongly reduced caspase activity and maintained the physiological pH compared to untreated tissues. Thus, dopamine and serotonin protect cells against hypothermia/rewarming induced damage by increasing H(2)S production mediated through CBS. Our data identify a novel molecular link between biogenic amines and the H(2)S pathway, which may profoundly affect our understanding of the biological effects of monoamine neurotransmitters.     

The effect of climate change on the resilience of ecosystems with adaptive spatial pattern formation

In a rapidly changing world, quantifying ecosystem resilience is an important challenge. Historically, resilience has been defined via models that do not take spatial effects into account. These systems can only adapt via uniform adjustments. In reality, however, the response is not necessarily uniform, and can lead to the formation of (self‐organised) spatial patterns – typically localised vegetation patches. Classical measures of resilience cannot capture the emerging dynamics in spatially self‐organised systems, including transitions between patterned states that have limited impact on ecosystem structure and productivity. We present a framework of interlinked phase portraits that appropriately quantifies the resilience of patterned states, which depends on the number of patches, the distances between them and environmental conditions. We show how classical resilience concepts fail to distinguish between small and large pattern transitions, and find that the variance in interpatch distances provides a suitable indicator for the type of imminent transition. Subsequently, we describe the dependency of ecosystem degradation based on the rate of climatic change: slow change leads to sporadic, large transitions, whereas fast change causes a rapid sequence of smaller transitions. Finally, we discuss how pre‐emptive removal of patches can minimise productivity losses during pattern transitions, constituting a viable conservation strategy.     

18F-Fluorodeoxyglucose Positron Emission Tomography in Elderly Patients with an Elevated Erythrocyte Sedimentation Rate of Unknown Origin

Patients with an elevated erythrocyte sedimentation rate (ESR) and non-specific symptoms often pose a diagnostic dilemma. PET/CT visualises infection, inflammation and malignancy, all of which may cause elevated ESR. The objective of this study was to determine the contribution of 18F-fluorodeoxglucose positron emission tomography (PET/CT) in the diagnostic work-up of referred patients with an elevated ESR, in whom initial routine evaluation did not reveal a diagnosis. We conducted a combined retrospective (A) and prospective (B) study in elderly (>50 years) patients with a significantly elevated ESR of≥50 mm/h and non-specific complaints. In study A, 30 patients were included. Malignancy (8 patients), auto-inflammatory disease (8 patients, including 5 with large-vessel vasculitis) and infection (3 patients) were suggested by PET/CT. Two scans showed non-specific abnormalities and 9 scans were normal. Of the 21 abnormal PET/CT results, 12 diagnoses were independently confirmed and two alternative diagnosis were made. Two diagnoses were established in patients with a normal scan. In study B, 58 patients in whom a prior protocolised work-up was non-diagnostic, were included. Of these, 25 PET/CT-scans showed suspected auto-inflammatory disease, particularly large-vessel vasculitis (14 cases). Infection and malignancy was suspected in 5 and 3 cases, respectively. Seven scans demonstrated non-specific abnormalities, 20 were normal. Of the 40 abnormal PET/CT results, 22 diagnoses were confirmed, 3 alternative diagnoses were established. Only one diagnosis was established in the 20 patients with a normal scan. In both studies, the final diagnosis was based on histology, clinical follow-up, response to therapy or additional imaging. In conclusion, PET/CT may be of potential value in the diagnostic work-up of patients with elevated ESR if routine evaluation reveals no diagnosis. In particular, large-vessel vasculitis appears to be a common finding. A normal PET/CT scan in these patients suggests that it is safe to follow a wait-and-see policy.     

Drug Users in Amsterdam: Are They Still at Risk for HIV?

Background and Aims

To examine whether drug users (DU) in the Amsterdam Cohort Study (ACS) are still at risk for HIV, we studied trends in HIV incidence and injecting and sexual risk behaviour from 1986 to 2011.

Methods

The ACS is an open, prospective cohort study on HIV. Calendar time trends in HIV incidence were modelled using Poisson regression. Trends in risk behaviour were modelled via generalized estimating equations. In 2010, a screening for STI (chlamydia, gonorrhoea and syphilis) was performed. Determinants of unprotected sex were studied using logistic regression analysis.

Results

The HIV incidence among 1298 participants of the ACS with a total follow-up of 12,921 person-years (PY) declined from 6.0/100 PY (95% confidence interval [CI] 3.2–11.1) in 1986 to less than 1/100 PY from 1997 onwards. Both injection and sexual risk behaviour declined significantly over time. Out of 197 participants screened for STI in 2010–2011, median age 49 years (IQR 43–59), only 5 (2.5%) were diagnosed with an STI. In multivariable analysis, having a steady partner (aOR 4.1, 95% CI 1.6–10.5) was associated with unprotected sex. HIV-infected participants were less likely to report unprotected sex (aOR 0.07, 95% CI 0.02–0.37).

Conclusions

HIV incidence and injection risk behaviour declined from 1986 onwards. STI prevalence is low; unprotected sex is associated with steady partners and is less common among HIV-infected participants. These findings indicate a low transmission risk of HIV and STI, which suggests that DU do not play a significant role in the current spread of HIV in Amsterdam.     

Evaluating the ecological realism of plant species distribution models with ecological indicator values

Species distribution models (SDMs) are routinely applied to assess current as well as future species distributions, for example to assess impacts of future environmental change on biodiversity or to underpin conservation planning. It has been repeatedly emphasized that SDMs should be evaluated based not only on their goodness of fit to the data, but also on the realism of the modeled ecological responses. However, possibilities for the latter are hampered by limited knowledge on the true responses as well as a lack of quantitative evaluation methods. Here we compared modeled niche optima obtained from European-scale SDMs of 1476 terrestrial vascular plant species with empirical ecological indicator values indicating the preferences of plant species for key environmental conditions. For each plant species we first fitted an ensemble SDM including three modeling techniques (GLM, GAM and BRT) and extracted niche optima for climate, soil, land use and nitrogen deposition variables with a large explanatory power for the occurrence of that species. We then compared these SDM-derived niche optima with the ecological indicator values by means of bivariate correlation analysis. We found weak to moderate correlations in the expected direction between the SDM-derived niche optima and ecological indicator values. The strongest correlation occurred between the modeled optima for growing degree days and the ecological indicator values for temperature. Correlations were weaker for SDM-derived niche optima with a more distal relationship to ecological indicator values (notably precipitation and soil moisture). Further, correlations were consistently highest for BRT, followed by GLM and GAM. Our method gives insight into the ecological realism of modeled niche optima and projected core habitats and can be used to improve SDMs by making a more informed selection of environmental variables and modeling techniques.     

Regulation of jasmonate metabolism and activation of systemic signaling in Solanum nigrum: COI1 and JAR4 play overlapping yet distinct roles

? Understory plants are subjected to highly intermittent light availability and their leaf gas exchanges are mediated by delayed responses of stomata and leaf biochemistry to light fluctuations. In this article, the patterns in stomatal delays across biomes and plant functional types were studied and their effects on leaf carbon gains and water losses were quantified. ? A database of more than 60 published datasets on stomatal responses to light fluctuations was assembled. To interpret these experimental observations, a leaf gas exchange model was developed and coupled to a novel formulation of stomatal movement energetics. The model was used to test whether stomatal delays optimize light capture for photosynthesis, whilst limiting transpiration and carbon costs for stomatal movement. ? The data analysis showed that stomatal opening and closing delays occurred over a limited range of values and were strongly correlated. Plant functional type and climate were the most important drivers of stomatal delays, with faster responses in graminoids and species from dry climates. ? Although perfectly tracking stomata would maximize photosynthesis and minimize transpiration at the expense of large opening costs, the observed combinations of opening and closure times appeared to be consistent with a near-optimal balance of carbon gain, water loss and movement costs.     

Finding the Needles in the Metagenome Haystack

In the collective genomes (the metagenome) of the microorganisms inhabiting the Earth’s diverse environments is written the history of life on this planet. New molecular tools developed and used for the past 15 years by microbial ecologists are facilitating the extraction, cloning, screening, and sequencing of these genomes. This approach allows microbial ecologists to access and study the full range of microbial diversity, regardless of our ability to culture organisms, and provides an unprecedented access to the breadth of natural products that these genomes encode. However, there is no way that the mere collection of sequences, no matter how expansive, can provide full coverage of the complex world of microbial metagenomes within the foreseeable future. Furthermore, although it is possible to fish out highly informative and useful genes from the sea of gene diversity in the environment, this can be a highly tedious and inefficient procedure. Microbial ecologists must be clever in their pursuit of ecologically relevant, valuable, and niche-defining genomic information within the vast haystack of microbial diversity. In this report, we seek to describe advances and prospects that will help microbial ecologists glean more knowledge from investigations into metagenomes. These include technological advances in sequencing and cloning methodologies, as well as improvements in annotation and comparative sequence analysis. More significant, however, will be ways to focus in on various subsets of the metagenome that may be of particular relevance, either by limiting the target community under study or improving the focus or speed of screening procedures. Lastly, given the cost and infrastructure necessary for large metagenome projects, and the almost inexhaustible amount of data they can produce, trends toward broader use of metagenome data across the research community coupled with the needed investment in bioinformatics infrastructure devoted to metagenomics will no doubt further increase the value of metagenomic studies in various environments.     

Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex

Nicotine enhances attention and working memory by activating nicotinic acetylcholine receptors (nAChRs). The prefrontal cortex (PFC) is critical for these cognitive functions and is also rich in nAChR expression. Specific cellular and synaptic mechanisms underlying nicotine's effects on cognition remain elusive. Here we show that nicotine exposure increases the threshold for synaptic spike-timing-dependent potentiation (STDP) in layer V pyramidal neurons of the mouse PFC. During coincident presynaptic and postsynaptic activity, nicotine reduces dendritic calcium signals associated with action potential propagation by enhancing GABAergic transmission. This results from a series of presynaptic actions involving different PFC interneurons and multiple nAChR subtypes. Pharmacological block of nAChRs or GABA(A) receptors prevented nicotine's actions and restored STDP, as did increasing dendritic calcium signals with stronger postsynaptic activity. Thus, by activating nAChRs distributed throughout the PFC neuronal network, nicotine affects PFC information processing and storage by increasing the amount of postsynaptic activity necessary to induce STDP.