Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.

Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.

Manual reaction times and brain dynamics after 'awake surgery' of slow-growing tumors invading the parietal area. A case report

Primary objectives: Awake surgeries of slow-growing tumours invading the brain and guided by direct electrical stimulation induce major brain reorganizations accompanied with slight impairments post-operatively. In most cases, these deficits are so slight after a few days that they are often not detectable on classical neuropsychological evaluations. Consequently, this study investigated whether simple visuo-manual reaction time paradigms would sign some level of functional asymmetries between both hemispheres. Importantly, the visual stimulus was located in the saggital plane in order to limit attentional biases and to focus mainly on the inter-hemispheric asymmetry. Methods and procedures: Three patients (aged 41, 59 and 59 years) after resections in parietal regions and a control group (age¼44, SD¼6.9) were compared during simple uni- and bimanual reaction times (RTs). Main outcomes and results: Longer RTs were observed for the contralesional compared to the ipsilesional hand in the unimanual condition. This asymmetry was reversed for the bimanual condition despite longer RTs. Conclusion and clinical implications: Reaction time paradigms are useful in these patients to monitor more precisely their functional deficits, especially their level of functional asymmetry, and to understand brain (re)organization following slowgrowing lesions.

Improving Safety for Slow Moving Vehicles on Iowa's High-Speed Rural Roadways, TR-572, 2009

Among the variety of road users and vehicle types that travel on U.S. public roadways, slow moving vehicles (SMVs) present unique safety and operations issues. SMVs include vehicles that do not maintain a constant speed of 25 mph, such as large farm equipment, construction vehicles, or horse-drawn buggies. Though the number of crashes involving SMVs is relatively small, SMV crashes tend to be severe. Additionally, SMVs can be encountered regularly on non-Interstate/non-expressway public roadways, but motorists may not be accustomed to these vehicles. This project was designed to improve transportation safety for SMVs on Iowa’s public roadway system. This report includes a literature review that shows various SMV statistics and laws across the United States, a crash study based on three years of Iowa SMV crash data, and recommendations from the SMV community.

The slow transformation of Swiss federal administrative elites

This article sets out to study the profile of Swiss administrative elites at federal level by showing how their profile has evolved in the light of what has come to be known as the wave of New Public Management (NPM), which has benefited from a very fertile ground in Switzerland. These elites correspond to a specific institutional order, in relation to specific organizational structures and workings, and have specific characteristics in terms of career paths and academic background. However, the administrative reforms that have been rolled out since the 1980s have transformed the institutional order within which executives of the federal administration evolve. This article analyses the extent to which these transformations have had an impact on the characteristics of these elites, through indicators such as academic capital, social capital, and career path within and outside the administration. The results show a slow but significant transformation in the profiles of these elites towards an increasing managerialization, reflecting that of the context in which they evolve.Points for practitioners The relationship between politics and the administration is naturally shaped by individuals but is closely dependent on the profiles of the players. They are currently undergoing a transformation in the wake of administrative reforms, and also of the changing profiles of both the political and administrative players. Gaining an insight into the slow transformation of the profiles of administrative elites therefore sheds light on the political-administrative nexus. The gradual managerialization of the administrative elite highlighted in this article also allows for a better understanding of which professional experiences, qualifications and skills are valued today within the senior civil service in Switzerland.

Senescence rates are determined by ranking on the fast-slow life-history continuum.

Comparative analyses of survival senescence by using life tables have identified generalizations including the observation that mammals senesce faster than similar-sized birds. These generalizations have been challenged because of limitations of life-table approaches and the growing appreciation that senescence is more than an increasing probability of death. Without using life tables, we examine senescence rates in annual individual fitness using 20 individual-based data sets of terrestrial vertebrates with contrasting life histories and body size. We find that senescence is widespread in the wild and equally likely to occur in survival and reproduction. Additionally, mammals senesce faster than birds because they have a faster life history for a given body size. By allowing us to disentangle the effects of two major fitness components our methods allow an assessment of the robustness of the prevalent life-table approach. Focusing on one aspect of life history - survival or recruitment - can provide reliable information on overall senescence.

In vitro conservation of Piper aduncum and Piper hispidinervum under slow-growth conditions

The objective of this work was to evaluate in vitro storage of Piper aduncum and P. hispidinervum under slow-growth conditions. Shoots were stored at low temperatures (10, 20 and 25°C), and the culture medium was supplemented with osmotic agents (sucrose and mannitol - at 1, 2 and 3%) and abiscisic acid - ABA (0, 0.5, 1.0, 2.0 and 3.0 mg L-1). After six-months of storage, shoots were evaluated for survival and regrowth. Low temperature at 20ºC was effective for the in vitro conservation of P. aduncum and P. hispidinervum shoots. In vitro cultures maintained at 20ºC on MS medium showed 100% survival with slow-growth shoots. The presence of mannitol or ABA, in the culture medium, negatively affected shoot growth, which is evidenced by the low rate of recovered shoots.

Effects of prior short multiple-sprint exercises with different intersprint recoveries on the slow component of oxygen uptake during high-intensity exercise.

This study compares the effects of two short multiple-sprint exercise (MSE) (6 × 6 s) sessions with two different recovery durations (30 s or 180 s) on the slow component of oxygen uptake ([Formula: see text]O(2)) during subsequent high-intensity exercise. Ten male subjects performed a 6-min cycling test at 50% of the difference between the gas exchange threshold and [Formula: see text]O(2peak) (Δ50). Then, the subjects performed two MSEs of 6 × 6 s separated by two intersprint recoveries of 30 s (MSE(30)) and 180 s (MSE(180)), followed 10 min later by the Δ50 (Δ50(30) and Δ50(180), respectively). Electromyography (EMG) activities of the vastus medialis and lateralis were measured throughout each exercise bout. During MSE(30), muscle activity (root mean square) increased significantly (p ≤ 0.04), with a significant leftward-shifted median frequency of the power density spectrum (MDF; p ≤ 0.01), whereas MDF was significantly rightward-shifted during MSE(180) (p = 0.02). The mean [Formula: see text]O(2) value was significantly higher in MSE(30) than in MSE(180) (p < 0.001). During Δ50(30), [Formula: see text]O(2) and the deoxygenated hemoglobin ([HHb]) slow components were significantly reduced (-27%, p = 0.02, and -34%, p = 0.003, respectively) compared with Δ50. There were no significant modifications of the [Formula: see text]O(2) slow component in Δ50(180) compared with Δ50 (p = 0.32). The neuromuscular and metabolic adaptations during MSE(30) (preferential activation of type I muscle fibers evidenced by decreased MDF and a greater aerobic metabolism contribution to the required energy demands), but not during MSE(180), may lead to reduced [Formula: see text]O(2) and [HHb] slow components, suggesting an alteration in motor units recruitment profile (i.e., change in the type of muscle fibers recruited) and (or) an improved muscle O(2) delivery during subsequent exercise.

In vitro maintenance, under slow-growth conditions, of oil palm germplasm obtained by embryo rescue

The objective of this work was to evaluate the in vitro maintenance of oil palm (Elaeis guineensis and E. oleifera) accessions under slow-growth conditions. Plants produced by embryo rescue were subject to 1/2MS culture medium supplemented with the carbohydrates sucrose, mannitol, and sorbitol at 1, 2, and 3% under 20 and 25±2ºC. After 12 months, the temperature of 20°C reduced plant growth. Sucrose is the most appropriate carbohydrate for maintaining the quality of the plants, whereas mannitol and sorbitol result in a reduced plant survival.

Two distinct plant respiratory physiotypes might exist which correspond to fast-growing and slow-growing species

The origin of the carbon atoms in CO2 respired by leaves in the dark of several plant species has been studied using 13C/12C stable isotopes. This study was conducted using an open gas exchange system for isotope labeling that was coupled to an elemental analyser and further linked to an isotope ratio mass spectrometer (EA-IRMS) or coupled to a gas chromatography-combustion-isotope ratio mass spectrometer (GC-C-IRMS). We demonstrate here that the carbon, which is recently assimilated during photosynthesis, accounts for nearly ca. 50% of the carbon in the CO2 lost through dark respiration after illumination in fast-growing and cultivated plants and trees and, accounts for only ca. 10% in slow-growing plants. Moreover, our study shows that fast- growing plants, which had the largest percentages of newly fixed carbon of leaf-respired CO2 , were also those with the largest shoot/root ratios, whereas slow-growing plants showed the lowest shoot/root values.

Synaptic depression and slow oscillatory activity in a biophysical network model of the cerebral cortex

Short-term synaptic depression (STD) is a form of synaptic plasticity that has a large impact on network computations. Experimental results suggest that STD is modulated by cortical activity, decreasing with activity in the network and increasing during silent states. Here, we explored different activity-modulation protocols in a biophysical network model for which the model displayed less STD when the network was active than when it was silent, in agreement with experimental results. Furthermore, we studied how trains of synaptic potentials had lesser decay during periods of activity (UP states) than during silent periods (DOWN states), providing new experimental predictions. We next tackled the inverse question of what is the impact of modifying STD parameters on the emergent activity of the network, a question difficult to answer experimentally. We found that synaptic depression of cortical connections had a critical role to determine the regime of rhythmic cortical activity. While low STD resulted in an emergent rhythmic activity with short UP states and long DOWN states, increasing STD resulted in longer and more frequent UP states interleaved with short silent periods. A still higher synaptic depression set the network into a non-oscillatory firing regime where DOWN states no longer occurred. The speed of propagation of UP states along the network was not found to be modulated by STD during the oscillatory regime; it remained relatively stable over a range of values of STD. Overall, we found that the mutual interactions between synaptic depression and ongoing network activity are critical to determine the mechanisms that modulate cortical emergent patterns.

An active zone characterized by slow normal faults, the northwestern margin of the València trough (NE Iberia): a review

The northwestern margin of the Valencia trough is an area of low strain characterized by slow normal faults and low to moderate seismicity. Since the mid 1990s this area has been the subject of a number of studies on active tectonic which have proposed different approaches to the location of active faults and to the calculation of the parameters that describe their seismic cycle. Fifty-six active faults have been found and a classification has been made in accordance with their characteristics: a) faults with clear evidence of large paleo-, historic or instrumental earthquakes (2/56); b) faults with evidence of accumulated activity during the Plio-Quaternary and with associated instrumental seismicity (7/56); c) faults with evidence of accumulated activity during the Plio-Quaternary and without associated instrumental seismicity (17/56); d) faults with associated instrumental seismicity and without evidence of accumulated activity during the Plio-Quaternary (30/56), and e) faults without evidence of activity or inactive faults. The parameters that describe the seismic cycle of these faults have been evaluated by different methods that use the geological data obtained for each fault except when paleoseismological studies were available. This classification can be applied to other areas with low slip faults because of the simplicity of the approaches adopted. This study reviews the different approaches proposed and describes the active faults located, highlighting the need a) to better understand active faults in slow strain zones through paleoseismological studies, and b) to include them in seismic hazard studies.