Ca2+-dependent repair of pneumolysin pores: A new paradigm for host cellular defense against bacterial pore-forming toxins

Pneumolysin (PLY), a key virulence factor of Streptococcus pneumoniae, permeabilizes eukaryotic cells by forming large trans-membrane pores. PLY imposes a puzzling multitude of diverse, often mutually excluding actions on eukaryotic cells. Whereas cytotoxicity of PLY can be directly attributed to the pore-mediated effects, mechanisms that are responsible for the PLY-induced activation of host cells are poorly understood. We show that PLY pores can be repaired and thereby PLY-induced cell death can be prevented. Pore-induced Ca2+ entry from the extracellular milieu is of paramount importance for the initiation of plasmalemmal repair. Nevertheless, active Ca2+ sequestration that prevents excessive Ca2+ elevation during the execution phase of plasmalemmal repair is of no less importance. The efficacy of plasmalemmal repair does not only define the fate of targeted cells but also intensity, duration and repetitiveness of PLY-induced Ca2+ signals in cells that were able to survive after PLY attack. Intracellular Ca2+ dynamics evoked by the combined action of pore formation and their elimination mimic the pattern of receptor-mediated Ca2+ signaling, which is responsible for the activation of host immune responses. Therefore, we postulate that plasmalemmal repair of PLY pores might provoke cellular responses that are similar to those currently ascribed to the receptor-mediated PLY effects. Our data provide new insights into the understanding of the complexity of cellular non-immune defense responses to a major pneumococcal toxin that plays a critical role in the establishment and the progression of life-threatening diseases. Therapies boosting plasmalemmal repair of host cells and their metabolic fitness might prove beneficial for the treatment of pneumococcal infections.

After Bali: WTO Rules Applying to Public Food Reserves

Once more, agriculture threatened to prevent all progress in multilateral trade rule-making at the Ninth WTO Ministerial Conference in December 2013. But this time, the “magic of Bali” worked. After the clock had been stopped mainly because of the food security file, the ministers adopted a comprehensive package of decisions and declarations mainly in respect of development issues. Five are about agriculture. Decision 38 on Public Stockholding for Food Security Purposes contains a “peace clause” which will now be shielding certain stockpile programmes from subsidy complaints in formal litigation. This article provides contextual background and analyses this decision from a legal perspective. It finds that, at best, Decision 38 provides a starting point for a WTO Work Programme for food security, for review at the Eleventh Ministerial Conference which will probably take place in 2017. At worst, it may unduly widen the limited window for government-financed competition existing under present rules in the WTO Agreement on Agriculture – yet without increasing global food security or even guaranteeing that no subsidy claims will be launched, or entertained, under the WTO dispute settlement mechanism. Hence, the Work Programme should find more coherence between farm support and socio-economic and trade objectives when it comes to stockpiles. This also encompasses a review of the present WTO rules applying to other forms of food reserves and to regional or “virtual” stockpiles. Another “low hanging fruit” would be a decision to exempt food aid purchases from export restrictions.

BrainCheck - a very brief tool to detect incipient cognitive decline: optimized case-finding combining patient- and informant-based data.

INTRODUCTION Optimal identification of subtle cognitive impairment in the primary care setting requires a very brief tool combining (a) patients' subjective impairments, (b) cognitive testing, and (c) information from informants. The present study developed a new, very quick and easily administered case-finding tool combining these assessments ('BrainCheck') and tested the feasibility and validity of this instrument in two independent studies. METHODS We developed a case-finding tool comprised of patient-directed (a) questions about memory and depression and (b) clock drawing, and (c) the informant-directed 7-item version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Feasibility study: 52 general practitioners rated the feasibility and acceptance of the patient-directed tool. Validation study: An independent group of 288 Memory Clinic patients (mean ± SD age = 76.6 ± 7.9, education = 12.0 ± 2.6; 53.8% female) with diagnoses of mild cognitive impairment (n = 80), probable Alzheimer's disease (n = 185), or major depression (n = 23) and 126 demographically matched, cognitively healthy volunteer participants (age = 75.2 ± 8.8, education = 12.5 ± 2.7; 40% female) partook. All patient and healthy control participants were administered the patient-directed tool, and informants of 113 patient and 70 healthy control participants completed the very short IQCODE. RESULTS Feasibility study: General practitioners rated the patient-directed tool as highly feasible and acceptable. Validation study: A Classification and Regression Tree analysis generated an algorithm to categorize patient-directed data which resulted in a correct classification rate (CCR) of 81.2% (sensitivity = 83.0%, specificity = 79.4%). Critically, the CCR of the combined patient- and informant-directed instruments (BrainCheck) reached nearly 90% (that is 89.4%; sensitivity = 97.4%, specificity = 81.6%). CONCLUSION A new and very brief instrument for general practitioners, 'BrainCheck', combined three sources of information deemed critical for effective case-finding (that is, patients' subject impairments, cognitive testing, informant information) and resulted in a nearly 90% CCR. Thus, it provides a very efficient and valid tool to aid general practitioners in deciding whether patients with suspected cognitive impairments should be further evaluated or not ('watchful waiting').

Methodology for GPS Synchronization Evaluation with High Accuracy

Clock synchronization in the order of nanoseconds is one of the critical factors for time-based localization. Currently used time synchronization methods are developed for the more relaxed needs of network operation. Their usability for positioning should be carefully evaluated. In this paper, we are particularly interested in GPS-based time synchronization. To judge its usability for localization we need a method that can evaluate the achieved time synchronization with nanosecond accuracy. Our method to evaluate the synchronization accuracy is inspired by signal processing algorithms and relies on fine grain time information. The method is able to calculate the clock offset and skew between devices with nanosecond accuracy in real time. It was implemented using software defined radio technology. We demonstrate that GPS-based synchronization suffers from remaining clock offset in the range of a few hundred of nanoseconds but the clock skew is negligible. Finally, we determine a corresponding lower bound on the expected positioning error.

Too exhausted for Operation? Anxiety, depleted self-control strength, and perceptual-motor performance

We tested the hypothesis that the interaction of self-control strength and state anxiety predicts perceptual–motor performance in a hand–eye coordination task. We predicted a stronger negative relation between anxiety and performance in a perceptual–motor task for participants whose self-control strength had been temporarily depleted compared to participants whose self-control strength was intact. In an experiment (N = 60), we manipulated self-control strength, measured state anxiety after an evaluative instruction, and assessed performance in the board game Operation as an indicator of perceptual–motor performance. The data supported our hypothesis: Only for participants whose self-control strength was temporarily depleted was there a statistically significant negative relation between anxiety and performance. Boosting self-control strength may help to prevent the potentially negative anxiety effects.

Transdiaphragmatic Resuscitative Open Cardiac Massage: Description of the Technique and a First Case-Series of an Alternative Approach to the Heart

Abstract BACKGROUND: The purpose of this paper is to describe the transdiaphragmatic approach to the heart for open CPR in patients that arrest at laparotomy and to present a first case series of patients that have undergone this procedure. METHODS: All patients who had undergone intraperitoneal transdiaphragmatic open CPR between January 1, 2002 and December 31, 2012 were retrieved from the operation registry at Bern University Hospital, Switzerland. Transdiaphragmatic access to the heart is initiated with a 10-cm-long anterocaudal incision in the central tendon of the diaphragm--approximately at 2 o'clock. Internal cardiac compression through the diaphragmatic incision can be performed from both sides of the patient. From the right side of the patient, cardiac massage is performed with the right hand and vice versa. RESULTS: A total of six patients were identified that suffered cardiac arrest during laparotomy with open CPR performed through the transdiaphragmatic approach. Four patients suffered cardiac arrest during orthotopic liver transplantation and two trauma patients suffered cardiac arrest during damage control laparotomy. In three patients, cardiac activity was never reestablished. However, three patients regained a perfusion heart rhythm and two of these survived to the ICU. One patient ultimately survived to discharge. CONCLUSIONS: In patients suffering cardiac arrest during laparotomy, the transdiaphragmatic approach allows for a rapid, technically easy, and almost atraumatic access to the heart, with excellent CPR performance. After this potentially life-saving procedure, pulmonary or surgical site complications are expected to occur much less compared with the conventionally performed emergency department left-sided thoracotomy.

Elucidating the internal structure of psychophysical timing performance in the sub-second and second range by utilizing confirmatory factor analysis

The most influential theoretical account in time psychophysics assumes the existence of a unitary internal clock based on neural counting. The distinct timing hypothesis, on the other hand, suggests an automatic timing mechanism for processing of durations in the sub-second range and a cognitively controlled timing mechanism for processing of durations in the range of seconds. Although several psychophysical approaches can be applied for identifying the internal structure of interval timing in the second and sub-second range, the existing data provide a puzzling picture of rather inconsistent results. In the present chapter, we introduce confirmatory factor analysis (CFA) to further elucidate the internal structure of interval timing performance in the sub-second and second range. More specifically, we investigated whether CFA would rather support the notion of a unitary timing mechanism or of distinct timing mechanisms underlying interval timing in the sub-second and second range, respectively. The assumption of two distinct timing mechanisms which are completely independent of each other was not supported by our data. The model assuming a unitary timing mechanism underlying interval timing in both the sub-second and second range fitted the empirical data much better. Eventually, we also tested a third model assuming two distinct, but functionally related mechanisms. The correlation between the two latent variables representing the hypothesized timing mechanisms was rather high and comparison of fit indices indicated that the assumption of two associated timing mechanisms described the observed data better than only one latent variable. Models are discussed in the light of the existing psychophysical and neurophysiological data.

A comment on the article “A collinearity diagnosis of the GNSS geocenter determination” by P. Rebischung, Z. Altamimi, and T. Springer

Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) showed that the geocenter z -component estimated from observations of global navigation satellite systems (GNSS) is strongly correlated to a particular parameter of the solar radiation pressure (SRP) model developed by Beutler et al. (Manuscr Geod 19:367–386, 1994). They analyzed the forces caused by SRP and the impact on the satellites’ orbits. The authors achieved their results using perturbation theory and celestial mechanics. Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026, 2013) also deal with the geocenter determination with GNSS. The authors carried out a collinearity diagnosis of the associated parameter estimation problem. They conclude “without much exaggerating that current GNSS are insensitive to any component of geocenter motion”. They explain this inability by the high degree of collinearity of the geocenter coordinates mainly with satellite clock corrections. Based on these results and additional experiments, they state that the conclusions drawn by Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) are questionable. We do not agree with these conclusions and present our arguments in this article. In the first part, we review and highlight the main characteristics of the studies performed by Meindl et al. (Adv Space Res 51(7):1047–1064, 2013) to show that the experiments are quite different from those performed by Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026,2013) . In the second part, we show that normal equation (NEQ) systems are regular when estimating geocenter coordinates, implying that the covariance matrices associated with the NEQ systems may be used to assess the sensitivity to geocenter coordinates in a standard way. The sensitivity of GNSS to the components of the geocenter is discussed. Finally, we comment on the arguments raised by Rebischung et al. (J Geod doi:10.1016/j.asr.2012.10.026, 2013) against the results of Meindl et al. (Adv Space Res 51(7):1047–1064, 2013).

Role of Crop Research and Development in food Security of Africa

Food security is the main concern in Africa as the production and productivity of crops are under continuous threat. Indigenous crops also known as orphan- or as underutilized- crops provide key contributions to food security under the present scenario of increasing world population and changing climate. Hence, these crops which belong to the major categories of cereals, legumes, fruits and root crops play a key role in the livelihood of the resource-poor farmers and consumers since they perform better than the major world crops under extreme soil and climate conditions prevalent in the continent. These indigenous crops have the major advantage that they fit well into the general socio-economic and ecological context of the region. However, despite their huge importance, African crops have generally received little attention by the global scientific community. With the current production systems, only a fraction of yield potential was achieved for most of these crops. In order to devise strategies towards boosting crop productivity in Africa, the current production constraints should be investigated and properly addressed. Key traits known to increase productivity and/or improve nutrition and diverse conventional and modern crop improvement techniques need to be implemented. Commitments in the value-chain from the research, production, marketing to distribution of improved seeds are required by relevant national and international institutions as well as African governments to promote food security in a sustainable manner. The review also presents major achievements and suggestions for stakeholders interested in African agriculture.

Induced Jasmonate Signaling Leads to Contrasting Effects on Root Damage and Herbivore Performance

Induced defenses play a key role in plant resistance against leaf feeders. However, very little is known about the signals that are involved in defending plants against root feeders and how they are influenced by abiotic factors. We investigated these aspects for the interaction between rice (Oryza sativa) and two root-feeding insects: the generalist cucumber beetle (Diabrotica balteata) and the more specialized rice water weevil (Lissorhoptrus oryzophilus). Rice plants responded to root attack by increasing the production of jasmonic acid (JA) and abscisic acid, whereas in contrast to in herbivore-attacked leaves, salicylic acid and ethylene levels remained unchanged. The JA response was decoupled from flooding and remained constant over different soil moisture levels. Exogenous application of methyl JA to the roots markedly decreased the performance of both root herbivores, whereas abscisic acid and the ethylene precursor 1-aminocyclopropane-1-carboxylic acid did not have any effect. JA-deficient antisense 13-lipoxygenase (asLOX) and mutant allene oxide cyclase hebiba plants lost more root biomass under attack from both root herbivores. Surprisingly, herbivore weight gain was decreased markedly in asLOX but not hebiba mutant plants, despite the higher root biomass removal. This effect was correlated with a herbivore-induced reduction of sucrose pools in asLOX roots. Taken together, our experiments show that jasmonates are induced signals that protect rice roots from herbivores under varying abiotic conditions and that boosting jasmonate responses can strongly enhance rice resistance against root pests. Furthermore, we show that a rice 13-lipoxygenase regulates root primary metabolites and specifically improves root herbivore growth.

Plant strengtheners enhance parasitoid attraction to herbivore-damaged cotton via qualitative and quantitative changes in induced volatiles

BACKGROUND Herbivore-damaged plants release a blend of volatile organic compounds (VOCs) that differs from undamaged plants. These induced changes are known to attract the natural enemies of the herbivores and therefore are expected to be important determinants of the effectiveness of biological control in agriculture. One way of boosting this phenomenon is the application of plant strengtheners, which has been shown to enhance parasitoid attraction in maize. It is unclear whether this is also the case for other important crops. RESULTS The plant strengtheners BTH [benzo (1,2,3) thiadiazole-7-carbothioic acid S-methyl ester] and laminarin were applied to cotton plants, and the effects on volatile releases and the attraction of three hymenopteran parasitoids, Cotesia marginiventris, Campoletis sonorensis and Microplitis rufiventris, were studied. After treated and untreated plants were induced by real or simulated caterpillar feeding, it was found that BTH treatment increased the attraction of the parasitoids, whereas laminarin had no significant effect. BTH treatment selectively increased the release of two homoterpenes and reduced the emission of indole, the latter of which had been shown to interfere with parasitoid attraction in earlier studies. Canonical variate analyses of the data show that the parasitoid responses were dependent on the quality rather than the quantity of volatile emission in this tritrophic interaction. CONCLUSION Overall, these results strengthen the emerging paradigm that induction of plant defences with chemical elicitors such as BTH could provide a sustainable and environmentally friendly strategy for biological control of pests by enhancing the attractiveness of cultivated plants to natural enemies of insect herbivores. © 2014 Society of Chemical Industry

Detecting dementia in patients with normal neuropsychological screening by Short Smell Test and Palmo-Mental Reflex Test: an observational study

BACKGROUND General practitioners (GPs) are in best position to suspect dementia. Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT) are widely used. Additional neurological tests may increase the accuracy of diagnosis. We aimed to evaluate diagnostic ability to detect dementia with a Short Smell Test (SST) and Palmo-Mental Reflex (PMR) in patients whose MMSE and CDT are normal, but who show signs of cognitive dysfunction. METHODS This was a 3.5-year cross-sectional observational study in the Memory Clinic of the University Department of Geriatrics in Bern, Switzerland. Participating patients with normal MMSE (>26 points) and CDT (>5 points) were referred by GPs because they suspected dementia. All were examined according to a standardized protocol. Diagnosis of dementia was based on DSM-IV TR criteria. We used SST and PMR to determine if they accurately detected dementia. RESULTS In our cohort, 154 patients suspected of dementia had normal MMSE and CDT test results. Of these, 17 (11 %) were demented. If SST or PMR were abnormal, sensitivity was 71 % (95 % CI 44-90 %), and specificity 64 % (95 % CI 55-72 %) for detecting dementia. If both tests were abnormal, sensitivity was 24 % (95 % CI 7-50 %), but specificity increased to 93 % (95 % CI 88-97 %). CONCLUSION Patients suspected of dementia, but with normal MMSE and CDT results, may benefit if SST and PMR are added as diagnostic tools. If both SST and PMR are abnormal, this is a red flag to investigate these patients further, even though their negative neuropsychological screening results.

Differential recruitment of brain networks during visuospatial and color processing: Evidence from ERP microstates

Recent functional magnetic resonance imaging (fMRI) studies consistently revealed contributions of fronto-parietal and related networks to the execution of a visuospatial judgment task, the so-called "Clock Task". However, due to the low temporal resolution of fMRI, the exact cortical dynamics and timing of processing during task performance could not be resolved until now. In order to clarify the detailed cortical activity and temporal dynamics, 14 healthy subjects performed an established version of the "Clock Task", which comprises a visuospatial task (angle discrimination) and a control task (color discrimination) with the same stimulus material, in an electroencephalography (EEG) experiment. Based on the time-resolved analysis of network activations (microstate analysis), differences in timing between the angle compared to the color discrimination task were found after sensory processing in a time window starting around 200ms. Significant differences between the two tasks were observed in an analysis window from 192ms to 776ms. We divided this window in two parts: an early phase - from 192ms to ∼440ms, and a late phase - from ∼440ms to 776ms. For both tasks, the order of network activations and the types of networks were the same, but, in each phase, activations for the two conditions were dominated by differing network states with divergent temporal dynamics. Our results provide an important basis for the assessment of deviations in processing dynamics during visuospatial tasks in clinical populations.

Age- and Gender-related Disparities in Primary Percutaneous Coronary Interventions for Acute ST-segment elevation Myocardial Infarction.

BACKGROUND Previous analyses reported age- and gender-related differences in the provision of cardiac care. The objective of the study was to compare circadian disparities in the delivery of primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) according to the patient's age and gender. METHODS We investigated patients included into the Acute Myocardial Infarction in Switzerland (AMIS) registry presenting to one of 11 centers in Switzerland providing primary PCI around the clock, and stratified patients according to gender and age. FINDINGS A total of 4723 patients presented with AMI between 2005 and 2010; 1319 (28%) were women and 2172 (54%) were ≥65 years of age. More than 90% of patients <65 years of age underwent primary PCI without differences between gender. Elderly patients and particularly women were at increased risk of being withheld primary PCI (males adj. HR 4.91, 95% CI 3.93-6.13; females adj. HR 9.31, 95% CI 7.37-11.75) as compared to males <65 years of age. An increased risk of a delay in door-to-balloon time >90 minutes was found in elderly males (adj HR 1.66 (95% CI 1.40-1.95), p<0.001) and females (adj HR 1.57 (95% CI 1.27-1.93), p<0.001), as well as in females <65 years (adj HR 1.47 (95% CI 1.13-1.91), p = 0.004) as compared to males <65 years of age, with significant differences in circadian patterns during on- and off-duty hours. CONCLUSIONS In a cohort of patients with AMI in Switzerland, we observed discrimination of elderly patients and females in the circadian provision of primary PCI.

Time window for recanalization in basilar artery occlusion: Speculative synthesis.

Basilar artery occlusion (BAO) is one of the most devastating forms of stroke and few patients have good outcomes without recanalization. Most centers apply recanalization therapies for BAO up to 12-24 hours after symptom onset, which is a substantially longer time window than the 4.5 hours used in anterior circulation stroke. In this speculative synthesis, we discuss recent advances in BAO treatment in order to understand why and under which circumstances longer symptom duration might not necrotize the brainstem and turn therapeutic attempts futile. We raise the possibility that distinct features of the posterior circulation, e.g., highly developed, persistent collateral arterial network, reverse filling of the distal basilar artery, and delicate plasma flow siding the clot, might sustain brittle patency of brainstem perforators in the face of stepwise growth of the thrombus. Meanwhile, the tissue clock characterizing the rapid necrosis of a typical anterior circulation penumbra will not start. During this perilous time period, recanalization at any point would salvage the brainstem from eventual necrosis caused by imminent reinforcement and further building up of the clot.