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The sulfur biogeochemical cycle controls the sulfur dynamics in the soil. In contrast to almost all deposited sulfur leaching out in temperate catchments, approximately 80% of the deposited S is retained in the catchments in subtropical regions. However, the mechanisms for sulfur retention were unclear, hindering the understanding of potential threats of legacy sulfur with environmental changes. Here, we demonstrated that sulfate reduction (as sulfide fixed in soil) was a prominent yet overlooked mechanism for sulfur retention in addition to the widely recognized sulfate adsorption in soil, based on a study on soil sulfur storage and stable isotope signatures within entire soil profiles in a typical subtropical catchment in China. Using a dual‐isotopic model, the sulfate reduction flux was further determined to be 30% of the S deposition. Due to a lot of deposited sulfur fixed via sulfate reduction, the release of soil legacy sulfur would be less in response to decreasing sulfur deposition compared to the projections only considering adsorption. However, the remobilization of large amounts of reduced S should be regarded as a threat to the environment under climate change in the future. Plain Language Summary: Sulfur budget in catchments reveals substantial retention of around 80% of deposited sulfur in subtropical soils, mitigating acidification arising from heightened sulfur deposition. The substantial sulfur retention was previously ascribed to sulfate adsorption. However, our study unveils sulfate reduction as a prominent yet overlooked retention mechanism, evidenced by soil sulfur storage estimates and stable isotope signatures across complete soil profiles in a typical subtropical Chinese catchment. Sulfate adsorption displays reversibility with declining atmospheric deposition. However, sulfate reduction exhibits relatively stable except during periods of frequent drought attributed to climate change or the soil excavation induced by land‐use change. Key Points: A dual isotopic mass balance model was built to quantify the transformations of S in the ecosystemsSulfur retention accounted for approximately 80% of deposition based on the sulfur input–output budgets for 17 sites in subtropical ChinaSulfate reduction was a prominent mechanism for sulfur retention in addition to widely recognized sulfate adsorption [ABSTRACT FROM AUTHOR]

Human activities have released a large amount of nitric oxides (NOx) into the atmosphere, leading to elevated regional atmospheric NOx concentration and nitrogen (N) deposition. Several studies have observed a downward NOx or NOy (NOx and its oxidation products) flux to the forest canopy, but attributed it to the photochemical reactions and conversion from gaseous N to particulate N. Here, we focus on the possibility of NOx sink by forest canopy based on an observed downward NOx flux of 0.28 kg N ha−1 yr−1 in a temperate forest of northeastern China, using hourly monitoring of NOx fluxes. In combination with results from previous studies, we find that the downward NOx or NOy fluxes ranged from 0.2 to 1.4 kg N ha−1 yr−1 in temperate forests and from 5.3 to 8.5 kg N ha−1 yr−1 in subtropical forests and they were positively related to atmospheric NOx concentration, mean annual air temperature and annual precipitation across eight forest sites from around the world. If assuming 50% of downward NOx or NOy was directly taken up by the canopy, we estimate a NOx or NOy sink of 0.2 and 1.1 Tg N yr−1 by global respective temperate and subtropical forests, representing an effective scavenger of atmospheric NOx and a considerable N source to forests. We suggest that interception of NOx or NOy by forest canopy should be considered in global NOx budgets and their contribution to the global forest N pool in global Earth System's models. Plain Language Summary: Canopy interception of reactive N has gained wide attention in recent several years, however, its quantification is still unclear. In the present work, we demonstrate the NOx downward movement in a typical temperate forest in northeastern China was partially driven by canopy biological uptake, and then combined results of our in situ observation of canopy NOx flux with other existing 10 monitoring sites worldwide. We estimated an N input of 0.2 and 1.1 Tg N yr−1 in global respective temperate and subtropical forests via downward NOx movement, representing an effective scavenger of atmospheric NOx and a considerable N source to forests. Key Points: The potential importance of canopy NOx uptake by forests for atmospheric NOx concentration and forest N pools is unclearCombining present and previous study results, we estimated a canopy N input of 0.2–1.1 Tg yr−1 in global temperate and subtropical forestsWe suggest that interception of NOx by forest canopy should be considered in global NOx budgets and forest N pools [ABSTRACT FROM AUTHOR]

Background and purpose: COVID‐19 is associated with multiple neurological manifestations. The clinical presentation, trajectory, and treatment response for three cases of myoclonus during COVID‐19 infection, with no previous neurological disease, are decsribed. Metods: Analysis of cerebrospinal fluid from the cases using indirect immunohistochemistry. Results: Antibodies against rodent brain tissue, and similarities in staining patterns were observed, indicating the presence of antineuronal immunoglobulin G autoantibodies targeting astrocytes in the hippocampus. Conclusion: Our results demontrate cerebrospinal fluid antineuronal antibodies indicating an an autoimmune involvment in the pathogenesis in COVID‐19 associated myoclonus. [ABSTRACT FROM AUTHOR]

Elevated nitrogen (N) deposition and changes in reduced or oxidized component contribution greatly affect soil acidification. China has experienced a significant transformation of N deposition components from NHx to NOy over the past 40 years, but the effects of component transformation on soil acidification are poorly understood. Therefore, long‐term monitoring data and literature on N deposition, combined with the results of isotope experiments, were used to explore the contributions of different N forms on soil acidification in China's forests. Here, all processes related to NHx and NOy, including the transformation to NH4+ and NO3− and subsequent N cycling in the soil, were considered. We found that N‐induced soil acidification in 80% area of China's forests was dominated by NHx deposition, and the other areas (South China) were dominated by NOy deposition in 2010s. From 1980 to 2019, the average contribution of NHx was higher than that of NOy but the latter contribution continued to increase. Meanwhile, the results showed that soil acidification increased with the decrease of the ratio of NHx to NOy (RNHx/NOy), which is mainly because NOy is more easily leached in the form of NO3− than that of NHx under the influence of different plant preferences and soil retention rates, resulting in a higher net proton production of NOy. Our research has powerful implications for policymaking, provides a theoretical basis for formulating different N reduction policies in different regions, and points out that the synergistic effect of RNHx/NOy changes should be considered to alleviate soil acidification. Key Points: Most forest soil was dominated by the contribution of NHx deposition, causing soil acidificationThe contribution of NOy deposition to soil acidification increased continuously during 1980–2019Decreased ratio of NHx to NOy deposition has led to aggravated forest soil acidification [ABSTRACT FROM AUTHOR]

Erosion and associated soil degradation are major threats to cropland productivity on the steep slopes of the Ethiopian highlands. To limit erosion from cultivated land on sloping terrain, stone bunds for soil conservation have been used for decades, resulting in the formation of terraces. Although qualitatively well known, the difference in soil properties and crop performance between the upper and lower sections of the terraces (intra‐bund areas) has not been documented quantitatively. Here, we assess differences in soil properties of the plough layer and crop performance in the upper and lower sections of terraces in between stone bunds in southwest Ethiopia. A total of 27 terraces, with a length of 28.5–57 m and a distance of 6.5–14.7 m in between adjacent stone bunds, were sampled on six different farms during the 2018 and 2019 cropping seasons. The difference in soil properties was analysed using analysis of variance (ANOVA). Results showed that, in the lower section of a terrace, the concentration of soil organic carbon (18.6 g kg−1), total soil nitrogen (2.1 g kg−1) and exchangeable potassium (328 mg kg−1) was significantly greater (p <.01) than in the upper section. Also, grain yield and biomass of maize, teff, broad bean and sorghum were significantly greater (p <.05) in the lower section. This was particularly true for maize for which the yield in 2018 increased from 0.7 t ha−1 in the upper sections to 2.6 t ha−1 in the lower sections. Optimizing crop yields on terraces requires adaptive fertilizer application and crop choice. [ABSTRACT FROM AUTHOR]

Nitrogen (N) deposition in Europe and North America decreased in the 1990s, whereas N deposition in China began to decline in the early 2010s. The response of temperate forests to decreasing N deposition implied a delay recovery, but it remains unknown whether recovery in subtropical forests follows a similar trend. Therefore, the effects of decreased N deposition on N leaching were simulated in an N‐saturated forest in southwest China following ten years of N application 4.00 g N m−2 yr−1. The addition of N (NH4+ or NO3−) was stopped in 2014. In 2017, a single in‐situ 15N addition as NH4+ or NO3− was performed to trace the fate of N under reducing N deposition. Combining the monitoring results of the N fluxes and 15N fates, both the actual N leaching and contribution of a "new" N input to N leaching were significantly reduced in response to decreasing the N input. The termination of N addition resulted in immediate decreases in the N mineralization and immobilization rates, which were even lower than those in the control plots with moderate (naturally occurring) deposition reduction. The ratio of N leaching from mineralization was also reduced, implying the critical role of N mineralization in the recovery from N saturation. Because the forest was still N‐saturated, decreasing N deposition slightly reduced the N leaching to the gross N input ratio (including both N deposition and N mineralization). The significant decrease in the ratio and thus leaching recovery may occur due to a significant N deposition reduction. Key Points: 15N tracing experiments were carried out under both increasing and decreasing N deposition, to study the fate of NH4+ and NO3− separatelyAfter N deposition decreased, N leaching to N deposition ratio increased inversely and N mineralization delayed leaching recoveryN leaching to gross N input ratio decreased after N deposition declined in N‐saturated subtropical forest, in accord with temperate forest [ABSTRACT FROM AUTHOR]

Overgrazing has caused serious grassland soil deterioration and significant soil organic carbon (SOC) losses. Controlled grazing is recommended for restoring grassland and enhancing SOC stocks. Studies have suggested that, in particular, labile organic carbon (C) is a sensitive indicator for soil degradation and SOC recovery, but few studies of the effect of different grassland management practices have been published so far. Here, we investigate the effects of long‐term grazing exclusion and short‐term rotational grazing with different grazing intensities on labile SOC, including hot water extractable organic C (HWEC) and particulate organic C (POC), as well as potential N mineralization (Nmin) rate in soils (0–10 cm) of two grasslands in Xilinhot, Inner Mongolia. Treatments include long‐term (34 years) exclusion, medium‐term (21 years) exclusion and continuous grazing (ambient grazing) at one of the sites, and we investigate no grazing, light grazing, moderate grazing and high‐grazing intensity at the study site for rotational grazing. Our results show that grazing exclusion significantly enhances labile SOC stocks and potential Nmin rate compared to ambient grazing (e.g., POC stock at long‐ and medium‐term exclusion and ambient grazing are 5.71 ± 0.94 Mg C ha−1, 3.25 ± 0.30 Mg C ha−1 and 2.12 ± 0.38 Mg C ha−1, respectively). However, after two decades of exclusion, the potential for further C sequestration is limited. Five years of rotational grazing significantly enhances HWEC, but not POC and potential Nmin rate, when comparing the highest grazing intensity (1.88 sheep ha−1 yr−1) with grazing exclusion during the same period. We conclude that rotational grazing may be a viable alternative to exclusion, offering a more rational use of grassland without causing soil C loss. We also show that HWEC is a particularly sensitive labile SOC indicator and is tightly correlated to POC and potential Nmin rate. Highlights: We investigated effects of grazing exclusion and rotational grazing on labile soil organic carbon.Grazing exclusion increased labile SOC and the highest level appeared in medium‐term exclusion.Five years of high‐intensity rotational grazing increased HWEC with no significant effects on POC.Rotational grazing is a viable alternative to grazing exclusion management. [ABSTRACT FROM AUTHOR]

Rationale: Acidic subtropical forest soils that receive high atmospheric nitrogen (N) deposition have been identified as important sources of nitric oxide (NO). The relative importance of major processes producing NO is unclear. Methods: To partition NO sources, we conducted an in situ tracing experiment with 15NH4NO3 and NH415NO3 in well‐drained acid soils of an N‐saturated subtropical forest in Chongqing, southwest China. Results: In the 15NH4NO3 treatment, the 15N signature of NO emitted from the foot of the hillslope (Lower site) was similar to that of the NH4+ pool, indicating predominant autotrophic nitrification for NO formation. In the NH415NO3 treatment, the 15N enrichment of NO was smaller than that of the NO3− pool, suggesting minor contribution of denitrification to NO production (~15%). Conclusions: Nitrification is the main process responsible for NO emissions, even in monsoonal summers when soil water‐filled pore space values are relatively high. [ABSTRACT FROM AUTHOR]

Commonly, well‐drained forest soils are net methane (CH4) sinks, whereas poorly drained soils in groundwater discharge zones could contribute significant CH4 emissions. Climate change is projected to bring more summer precipitation extremes to subtropics, which may affect forest CH4 balance. Chinese forests often have a hilly topography with well‐drained hillslopes and pronounced groundwater discharge zones. Although different landscape elements are likely to have different source and sink functions for CH4, the climatic influence on CH4 budget at the catchment scale remains poorly studied. Here, we measured CH4 fluxes over three years along a topographic gradient in a subtropical forested catchment in SW China. CH4 fluxes exhibited a clear spatial pattern indicating moderate CH4 uptake or emission from the well‐drained soils on the hillslope (−5.8 to +1.0 kg CH4‐C·ha−1·year−1) and significant CH4 emission from the wetter soils in the groundwater discharge zone (94.3 to 479.5 kg CH4‐C·ha−1·year−1). Despite its small area contribution to the catchment (0.6%), the groundwater discharge zone emitted substantial amounts of CH4 in monsoonal summers, affecting the whole‐catchment budget. Hillslope soils showed weaker CH4 uptake or even turned into a small CH4 source under wet climatic conditions. Estimates of catchment‐scale CH4 budgets indicate that subtropical forest catchments can tip from a net CH4 sink in drier years to a net CH4 source in wetter years, highlighting the importance of interannual climate variabilities. Our findings suggest that subtropical forests under projected climate change could contribute a net CH4 source with consequences for the regional CH4 balance. Plain Language Summary: Forest soils are commonly believed to uptake methane from the atmosphere, which is an important process to counteract the growth of atmospheric methane level. However, sparsely distributed wet soils in forests could contribute transient but large methane emissions to atmosphere. Under climate change, methane emission from wet soils may significantly change the role of forest ecosystems in regional methane budgets. Therefore, for three years, we measured soil‐atmosphere exchange of methane in upper drier and lower wetter soils at a subtropical forest in Southwest China. Under the influence of Eastern Asian monsoon, we observed strong methane emissions from the wetter soils of the forest during summers, despite that these areas only account for a small part of the forest. In a wet year, methane uptake in drier soils decreased and methane emission in wetter soils increased. Taking into account the contributions of both wetter and drier soils, estimates of annual methane budgets suggest that the studied subtropical forest contributes a net emission of methane to the atmosphere in a wet year. This work highlights an overlooked source of methane for the subtropical region and provides insights into the future role of forest ecosystem in greenhouse gas budgets under climate change. Key Points: Soils in the groundwater discharge zone of subtropical forest catchments emit substantial amounts of CH4 during monsoonal summersWell‐drained hillslope soils contribute a small CH4 sink or source depending on climatic conditionsDespite small area of their groundwater discharge zones, subtropical forested catchments can act as a net CH4 source in a wet year [ABSTRACT FROM AUTHOR]

Increasing nitrogen (N) deposition in subtropical forests in south China causes N saturation, associated with significant nitrate (NO3−) leaching. Strong N attenuation may occur in groundwater discharge zones hydrologically connected to well‐drained hillslopes, as has been shown for the subtropical headwater catchment "TieShanPing", where dual NO3− isotopes indicated that groundwater discharge zones act as an important N sink and hotspot for denitrification. Here, we present a regional study reporting inorganic N fluxes over two years together with dual NO3− isotope signatures obtained in two summer campaigns from seven forested catchments in China, representing a gradient in climate and atmospheric N input. In all catchments, fluxes of dissolved inorganic N indicated efficient conversion of NH4+ to NO3− on well‐drained hillslopes, and subsequent interflow of NO3− over the argic B‐horizons to groundwater discharge zones. Depletion of 15N‐ and 18O–NO3− on hillslopes suggested nitrification as the main source of NO3−. In all catchments, except one of the northern sites, which had low N deposition rates, NO3− attenuation by denitrification occurred in groundwater discharge zones, as indicated by simultaneous 15N and 18O enrichment in residual NO3−. By contrast to the southern sites, the northern catchments lack continuous and well‐developed groundwater discharge zones, explaining less efficient N removal. Using a model based on 15NO3− signatures, we estimated denitrification fluxes from 2.4 to 21.7 kg N ha−1 year−1 for the southern sites, accounting for more than half of the observed N removal. Across the southern catchments, estimated denitrification scaled proportionally with N deposition. Together, this indicates that N removal by denitrification is an important component of the N budget of southern Chinese forests and that natural NO3− attenuation may increase with increasing N input, thus partly counteracting further aggravation of N contamination of surface waters in the region. [ABSTRACT FROM AUTHOR]

In China, as in other parts of the world, the emission and deposition of reactive nitrogen (N) have been reduced in recent years. Several decades of elevated N deposition in southwest China (40 to 60 kg ha−1 year−1) have resulted in extreme cases of N saturation, where N outputs are nearly equal to N inputs. Doubling N inputs using either NH4NO3 or NaNO3 fertilizer in a subtropical forest in Tieshanping, near Chongqing city in southwest China, caused an immediate doubling of N leaching (as NO3−). Reducing N inputs to ambient atmospheric deposition levels after 10 years of fertilization led to a rapid decrease in soil water NO3− concentration to levels similar to those in the reference plots that had not receive N fertilizer application. NO3− leaching via the soil water in the NH4NO3 plots was even lower than that in the NaNO3 plots or the reference plots, confirming the finding of a previous N‐fertilizing experiment that found that NH4+ deposition, in contrast to NO3− deposition, increased N retention in the forest ecosystem. The N sink remained for at least 2 years after the cessation of N addition. Even with reduced N inputs, ambient atmospheric N deposition caused significant acidification, buffered partly by SO42− sorption. Therefore, further abatement of reactive N emissions is necessary in the future. Key Points: Soil nitrogen leaching responded very rapidly to reducing nitrogen deposition in a nitrogen‐saturated forestSoil nitrogen leaching decreased faster with historically high ammonia deposition than nitrate deposition with the same nitrogen levelEven with reduced N input, the ambient atmospheric N deposition still caused significant acidification at the study site [ABSTRACT FROM AUTHOR]

Summary: Objective: The role of neuroinflammation in mesial temporal lobe epilepsy (MTLE), and how it relates to drug resistance, remains unclear. Expression levels of the inflammatory enzymes cyclooxygenase (COX)‐1 and COX‐2 have been found to be increased in animal models of epilepsy. Knowing the cellular expression of COX‐1 and COX‐2 is the key to understanding their functional role; however, only 3 studies have investigated COX‐2 expression in epilepsy in humans, and there are no reports on COX‐1. In addition, previous studies have shown that certain inflammatory proteins up‐regulate ATP binding cassette (ABC) transporter expression (thought to be responsible for drug resistance), but this relationship remains unclear in human tissue. This study sought to measure the expression of COX‐1, COX‐2, and translocator protein 18 kDa (TSPO, an inflammation biomarker acting as a positive control), as well as ABC transporters P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP), in brain tissue samples from people with drug‐resistant MTLE. Methods: Formalin‐fixed paraffin‐embedded surgical brain tissue was obtained from 33 patients with drug‐resistant MTLE. Multiplex immunofluorescence was used to quantify the expression and distribution of COX‐1, COX‐2, TSPO, P‐gp, and BCRP. Results: COX‐1 was expressed in microglia, and COX‐2 and TSPO were expressed in microglia and neurons. BCRP density correlated significantly with TSPO density, suggesting a potential relationship between inflammatory markers and efflux transporters. Significance: To the best of our knowledge, this study is the first to measure the cellular expression of COX‐1, COX‐2, and TSPO in microglia, astrocytes, and neurons in surgical brain tissue samples from patients with drug‐resistant MTLE. Further research is needed to determine the effects of the COX inflammatory pathway in epilepsy, and how it relates to the expression of the ABC transporters P‐gp and BCRP. [ABSTRACT FROM AUTHOR]

Abstract: Nitrous oxide (N2O) is a greenhouse gas that also plays the primary role in stratospheric ozone depletion. The use of nitrogen fertilizers is known as the major reason for atmospheric N2O increase. Empirical bottom‐up models therefore estimate agricultural N2O inventories using N loading as the sole predictor, disregarding the regional heterogeneities in soil inherent response to external N loading. Several environmental factors have been found to influence the response in soil N2O emission to N fertilization, but their interdependence and relative importance have not been addressed properly. Here, we show that soil pH is the chief factor explaining regional disparities in N2O emission, using a global meta‐analysis of 1,104 field measurements. The emission factor (EF) of N2O increases significantly (p < .001) with soil pH decrease. The default EF value of 1.0%, according to IPCC (Intergovernmental Panel on Climate Change) for agricultural soils, occurs at soil pH 6.76. Moreover, changes in EF with N fertilization (i.e. ΔEF) is also negatively correlated (p < .001) with soil pH. This indicates that N2O emission in acidic soils is more sensitive to changing N fertilization than that in alkaline soils. Incorporating our findings into bottom‐up models has significant consequences for regional and global N2O emission inventories and reconciling them with those from top‐down models. Moreover, our results allow region‐specific development of tailor‐made N2O mitigation measures in agriculture. [ABSTRACT FROM AUTHOR]

Chronically elevated deposition of reactive nitrogen (N), as ammonium (NH4+) and nitrate (NO3−), in subtropical forests with monsoonal climate has caused widespread N leaching in southern China. So far, little is known about the effect of further increases in N input and changes in the relative proportion of NH4+ and NO3− on turnover rate and fate of atmogenic N. Here we report a 15N tracer experiment in Tieshanping (TSP) forest, SW China, conducted as part of a long-term N fertilization experiment, using NH4NO3 and NaNO3, where effects of a doubling of monthly N inputs were compared. In June 2012, the regular N fertilizers were replaced by their 15N-labeled forms, viz., 15NH4NO3 and Na15NO3, as a single-dose addition. Mass balances of N for the initial 1.5 years following label addition showed that for both treatments, 70% to 80% of the annual N input was leached as NO3−, both at ambient and at double N input rates. This confirms the earlier reported extreme case of N saturation at TSP. The 15N, added as Na15NO3, showed recoveries of about 74% in soil leachates, indicating that NO3− input at TSP is subject to a rapid and nearly quantitative loss through direct leaching as a mobile anion. By contrast, recoveries of 15N in soil leachates of only 33% were found if added as 15NH4NO3. Much of the 15N was immobilized in the soil and to a lesser extent in the vegetation. Thus, immobilization of fresh N input is significantly greater if added as NH4+, than as NO3−. [ABSTRACT FROM AUTHOR]

Ca2+-sensor proteins are generally implicated in insulin release through SNARE interactions. Here, secretagogin, whose expression in human pancreatic islets correlates with their insulin content and the incidence of type 2 diabetes, is shown to orchestrate an unexpectedly distinct mechanism. Single-cell RNA-seq reveals retained expression of the TRP family members in β-cells from diabetic donors. Amongst these, pharmacological probing identifies Ca2+-permeable transient receptor potential vanilloid type 1 channels ( TRPV1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors. Accordingly, agonist stimulation of TRPV1s fails to rescue insulin release from pancreatic islets of glucose intolerant secretagogin knock-out(−/−) mice. However, instead of merely impinging on the SNARE machinery, reduced insulin availability in secretagogin−/− mice is due to β-cell loss, which is underpinned by the collapse of protein folding and deregulation of secretagogin-dependent USP9X deubiquitinase activity. Therefore, and considering the desensitization of TRPV1s in diabetic pancreata, a TRPV1-to-secretagogin regulatory axis seems critical to maintain the structural integrity and signal competence of β-cells. [ABSTRACT FROM AUTHOR]

In forests of the humid subtropics of China, chronically elevated nitrogen (N) deposition, predominantly as ammonium (NH4+), causes significant nitrate (NO3−) leaching from well-drained acid forest soils on hill slopes (HS), whereas significant retention of NO3− occurs in near-stream environments (groundwater discharge zones, GDZ). To aid our understanding of N transformations on the catchment level, we studied spatial and temporal variabilities of concentration and natural abundance (δ15N and δ18O) of nitrate (NO3−) in soil pore water along a hydrological continuum in the N-saturated Tieshanping (TSP) catchment, southwest China. Our data show that effective removal of atmogenic NH4+ and production of NO3− in soils on HS were associated with a significant decrease in δ15N-NO3−, suggesting efficient nitrification despite low soil pH. The concentration of NO3− declined sharply along the hydrological flow path in the GDZ. This decline was associated with a significant increase in both δ15N and δ18O of residual NO3−, providing evidence that the GDZ acts as an N sink due to denitrification. The observed apparent 15N enrichment factor ( ε) of NO3− of about −5‰ in the GDZ is similar to values previously reported for efficient denitrification in riparian and groundwater systems. Episode studies in the summers of 2009, 2010 and 2013 revealed that the spatial pattern of δ15N and δ18O-NO3− in soil water was remarkably similar from year to year. The importance of denitrification as a major N sink was also seen at the catchment scale, as largest δ15N-NO3− values in stream water were observed at lowest discharge, confirming the importance of the relatively small GDZ for N removal under base flow conditions. This study, explicitly recognizing hydrologically connected landscape elements, reveals an overlooked but robust N sink in N-saturated, subtropical forests with important implications for regional N budgets. [ABSTRACT FROM AUTHOR]

Background Failed restorations in primary teeth are not always re-restored. Is re-restoration not required anymore? Objective To compare survival rates of primary molars with intact and defective amalgam and ART restorations. Methods A total of 649 restored primary molars, of which 162 were assessed with defective restorations for mechanical reasons, from a cluster-randomised controlled clinical trial, were followed up over a period of 3.5 years. Restored primary molars, extracted because of dental sepsis or toothache, were considered a failure. Primary molars with defective restorations were followed up from the time they were assessed defective. Data were analysed using PHREG model with frailty correction, Wald test, t-test, and jackknife procedure. Results The survival rate of primary molars with intact restorations (96.3%) was statistically significantly higher than that of primary molars with defective restorations (75.9%) over a 3-year period ( P < 0.0001). Neither the effect of treatment protocol (amalgam or ART) ( P = 0.05) nor the type of surface (single or multiple) ( P = 0.73) was observed with respect to the survival rate of restored primary molars. Conclusions Survival rates for primary molars with intact and defective amalgam and ART restorations were high. The 3-year survival rate of primary molars with intact restorations was significantly higher than that of primary molars with defective restorations. [ABSTRACT FROM AUTHOR]

Objective The aim of the study was to evaluate the exfoliation pattern of primary molars treated according to three treatment protocols. The hypothesis tested was that there is no difference in the exfoliation pattern of primary molars treated according to conventional restorative treatment using amalgam ( CRT), atraumatic restorative treatment using high-viscosity glass-ionomer ( ART), and ultraconservative treatment ( UCT). The latter consisted of restoring small cavities with ART and cleaning medium/large nonrestored cavities daily with toothpaste/toothbrush under supervision. Methods A sample of 302 children aged 6-7 years from a suburban area of Brasilia was followed up for 3.5 years. The numbers of treated molars were 341 ( CRT), 244 ( ART), and 275 ( UCT). Exfoliation rates were obtained using the PHREG procedure. Differences between the three treatment protocol groups were tested using the Wald test. Results After 3.5 years, there was no difference over the exfoliation rates of all primary molars as 51.0% ( CRT), 48.7% ( ART), and 48.1% ( UCT) had exfoliated at the overall period ( P = 0.37). Teeth with multiple-surfaces treatment had exfoliated in a higher proportion than teeth with single-surface treatments for all the three treatment groups ( P = 0.04). Conclusion The three treatment protocols led to similar exfoliation patterns of all primary molars after 3.5 years. [ABSTRACT FROM AUTHOR]

A hierarchical hormonal cascade along the hypothalamic-pituitary-adrenal axis orchestrates bodily responses to stress. Although corticotropin-releasing hormone ( CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus ( PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagogin's Ca2+ sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogin's loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness. [ABSTRACT FROM AUTHOR]

In extensive farmer-led trials practicing conservation farming (CF) in three regions of Zambia (Mongu: sandy soils; Kaoma: sandy or loamy sand soils; Mkushi: sandy loam or loamy soils), we studied the effects of biochar made of maize cobs (0, 2, and 6 t ha−1 corresponding to 0, 0.8, and 2.5% per basin) at different fertilizer rates of NPK and urea on crop yield of maize ( Zea mays) and groundnuts ( Arachis hypogaea). Conservation farming in this case combines minimum tillage (how basins), crop rotation and residue retention. For the first time, the effect of biochar on in situ soil nutrient supply rates [determined by buried Plant Root Simulator (PRS™) exchange resins] was studied, as well as the effects of biochar on elemental composition of maize. Effects of 0-10% (w:w) biochar addition on soil physical and soil chemical properties were determined in the laboratory. At all sites there was a consistent positive response in crop yield upon the addition of biochar. However, due to a great variability between farms there were no significant differences in absolute yields between the treatments. In the sandy soils at Mongu, relative yields ( i.e., percentage yield with biochar relative to the same fertilizer rate without biochar) of maize grains and maize stover were significantly increased at recommended fertilizer rates (232 ± 60%) and at half the recommended rate (128 ± 6%), respectively. In addition, biochar significantly increased concentrations of K and P in maize stover. In situ soil nutrient supply rates as measured by PRS™-probes were highly spatially variable with no consistent effects of the different treatments in the three regions. By contrast, the fraction of plant available water (Vol.-%) significantly increased upon the addition of biochar in all three soils. The increase caused by 10% biochar addition was of factor 2.5 in Mongu (from 4.5% to 11.2%) and 1.2 in both Kaoma (from 14.7% to 18.2%) and Mkushi (from 18.2% to 22.7%). Cation exchange capacity, pH, and exchangeable K significantly increased upon the addition of 10% (w:w) biochar in all three regions with a subsequent increase in base saturation and decrease of available Al3+. Our findings suggest that the addition of biochar in combination with CF might have a positive impact on crop growth and that this positive effect is mainly caused by increases in plant-available water and decreased available Al. [ABSTRACT FROM AUTHOR]

This study investigated the effect of biochar amendments on the retention and availability of plant nutrients and Al in seven acidic tropical soils from Zambia and Indonesia. The experiments carried out investigated whether the adsorption capacity of NH $ _4^+ $ in the soils increased upon the addition of biochar and which effect biochar had on available concentrations of NO $ _3^- $, K+, Mn2+, Mg2+ , PO $ _4^{3‐} $, and Al3+. These nutrients were selected as they represent those important to plant growth and soil quality. No significant increases or decreases in aqueous NH $ _4^+ $-N concentration with additions of biochar were detected. The Gaines-Thomas model was used in order to calculate selectivity coefficients for NH $ _4^+ $ exchange (Kgt values). Following the addition of biochar to soil, Kgt values decreased showing a reduction in the selective binding of NH $ _4^+ $ in the biochar amended soil compared to the control. The concentration of NO $ _3^- $ increased following the addition of biochar to the soils. The addition of 5 and 10% biochar to the Indonesian soil did not significantly alter ( t-test confidence level 0.05) the sorption of PO $ _4^{3‐} $ to the soil-biochar mixtures as compared to the soil alone. However, the addition of biochar to the soil from Zambia increased the sorption of PO $ _4^{3‐} $ compared to the soil alone. The concentrations of K+ and Mg2+ were significantly increased for almost all soils ( t-test at the 0.05 confidence level) following the addition of biochar. Addition of biochar to all but two soils significantly decreased ( t-test confidence level 0.05) Mn2+ concentrations. The concentration of Al3+ in the soils decreased exponentially significantly ( t-test confidence level 0.05) following the amendment of biochar in accordance with the increase in pH observed when biochar was added to the soil. These results show that biochar has the ability to release essential plant growth nutrients as well as alleviate Al toxicity in these soils. [ABSTRACT FROM AUTHOR]

The article reviews the book "Sustainable Development, Evaluation and Policy-making: Theory, Practice and Quality Assurance" edited by Anneke von Raggamby and Frieder Rubik.

The article reviews the book "Roads from Rio: Lessons Learned from 20 Years of Multilateral Environmental Negotiations" edited by Pamela S. Chasek and Lynn M. Wagner.

Objectives: To assess attitudes, subjective norms, and intentions of primary health-care (PHC) providers in performing routine oral examination for oropharyngeal candidiasis (OPC) during outpatient consultations. Methods: A 47-item Theory of Planned Behaviour-based questionnaire was developed and administered, in a cross-sectional survey, to 216 PHC providers (clinical officers and nurses) working in 54 clinics, dispensaries, and health centers in Nairobi Province in January 2010. The constructs - attitudes, subjective norms, and perceived behavioral control (dependent variables) - and their individual indirect (direct) items were analyzed for scores, internal validity, independent variables (district, gender, years of service, profession, and age), and contribution to intentions. Perceived behavioral control had low construct validity and was therefore removed from subsequent analyses. Results: The questionnaire was completed by 195 participants (90 percent response rate). PHC provider's attitudes, subjective norms, and intentions to perform an oral examination during outpatient consultations were highly positive, with mean scores of 6.30 (0.82), 6.06 (1.07), and 5.6 (1.33), respectively, regardless of sociodemographic characteristics. Indirect attitude and subjective norms were strongly correlated to their individual items ( r = 0.63-0.79, P < 0.05 and r = 0.78-0.87, P < 0.05) and moderately to their direct items ( r = 0.44, P < 0.0001 and r = 0.52, P < 0.0001). Attitudes ( P = 0.0026) and subjective norms ( P < 0.0001) were both predictive of intentions. Conclusions: PHC providers were willing to integrate patients' oral health care into their routine medical consultations. Emphasizing the importance of detecting other oral problems and of the fact that routine oral examination for OPC is likely to give patients' fulfillment will enhance PHC providers' morale in performing routine oral examinations. Winning support from policy makers, their supervisors, specialists, and colleagues is important for motivating PHC providers to perform routine oral examinations for OPC at their workplaces. [ABSTRACT FROM AUTHOR]

In SW China, acid deposition has been associated with forest damage such as defoliation and mortality due to serious soil acidification. These effects may be exacerbated by ongoing climate change. Understanding the integrated effects of climate change and acid deposition on soil chemistry of forest ecosystems is the key to alleviate forest damage and recover forest health. In particular, the long-term development of integrated effects is unclear and, thus, prevents setting up cost-effective controls of atmospheric deposition for improved forest-health management. We employed the Nutrient Cycling Model (NuCM) to predict the changes of soil chemistry in a Masson pine ( Pinus massoniana) forest at Tie-Shan-Ping (nearby Chongqing, the biggest city in SW China) under two scenarios of climate change and five scenarios of atmospheric deposition. Field-monitoring data were used to calibrate and validate the NuCM model. It is shown that the maintaining of current acid deposition both in its quantity and composition would not enhance soil acidification although it would take further 20 years to reach a steady state with higher SO $ _4^{2-} $ and Ca2+ concentrations in soil solution. This simulated trend is in contradiction to the decrease of soil pH observed in field during last several decades. The possible reason of this may be the obviously elevated deposition of Ca2+, which may help to raise the pH of soil solution but occurred only in recent several years following the rapid increase of local construction industry. However, this enhanced Ca2+ input may not be maintained for long time. A decreased S input would lead to some positive effects on soil chemistry such as the increase of soil base saturation. A high N deposition has implicated the forest ecosystem to be saturated with N, and increased N input will further aggravate soil acidification and nutrient imbalances. The future climate change projected by IPCC, i.e., the increase of temperature and rainfall may slightly enhance the negative effect of increased N input. The integrated effect of climate change and N-deposition increase may counteract the positive effects of decreased S input to a considerable degree. This supports the need for a rigorous implementation of new technology to decrease the emission of both S and N. [ABSTRACT FROM AUTHOR]

In this article, the Strategic Environmental Assessment (SEA) Protocol to the Espoo Convention is introduced and analyzed. As an outcome of international processes aimed at the institutional adoption of sustainable development policy, the need for strategic environmental assessment has become obvious given the experiences with environmental impact assessment as an effective environmental policy tool for projects. The introduction of SEA and the adoption of a specific international legal instrument are also situated within ongoing international good governance and (new) public management developments which aim at improving decision making. In this context, the application of SEA and the SEA Protocol is analyzed focusing on its features, approaches and opportunities. [ABSTRACT FROM AUTHOR]

de Menezes Abreu DM, Leal SC, Mulder J, Frencken JE. Pain experience after conventional, atraumatic, and ultraconservative restorative treatments in 6- to 7-yr-old children. Eur J Oral Sci 2011; 119: 163-168. © 2011 Eur J Oral Sci The hypothesis was tested that the level of pain experienced by children during conventional restorative treatment is higher than during atraumatic restorative treatment (ART) or an ultraconservative treatment. The sample consisted of 244 children, 6- to 7 yr of age, who had at least two teeth with dentine carious lesions. Before the first treatment session (Tx-1), in which one of the carious teeth was treated using one of the treatments, the level of dental anxiety was assessed using the Facial Image Scale (FIS). The child reported the intensity of pain experienced during the procedure using the Wong-Baker FACES Pain Rating Scale. When conventional restorative treatment was used, more children needed local anaesthesia. Analyses excluding the data of children who had received local anaesthesia showed no treatment group effect on the Wong-Baker score, a FIS Tx-1 effect on the Wong-Baker score, and a statistically significant correlation between FIS Tx-1 and Wong-Baker scores. There was no significant difference in the pain levels of children treated using conventional restorative treatment, atraumatic restorative treatment or ultraconservative treatment. Local anaesthesia had to be administered more frequently to children in the conventional restorative group than to those in the other two treatment groups. [ABSTRACT FROM AUTHOR]

The article discusses the dispute between Argentina and Uruguay at the International Court of Justice (ICJ) in 2006. Argentina questioned Uruguay's decision in constructing a polluting paper mill at the Uruguay River without consultations since it may cause environmental damage. The ICJ ruled the the plant will continue to operate despite Uruguay's violation of a treaty that permitted them to construct but it informed Uruguay of its failure to inform Argentina of its plan to build the mill.

The Ca2+-binding proteins (CBPs) calbindin D28k, calretinin and parvalbumin are phenotypic markers of functionally diverse subclasses of neurons in the adult brain. The developmental dynamics of CBP expression are precisely timed: calbindin and calretinin are present in prospective cortical interneurons from mid-gestation, while parvalbumin only becomes expressed during the early postnatal period in rodents. Secretagogin (scgn) is a CBP cloned from pancreatic β and neuroendocrine cells. We hypothesized that scgn may be expressed by particular neuronal contingents during prenatal development of the mammalian telencephalon. We find that scgn is expressed in neurons transiting in the subpallial differentiation zone by embryonic day (E)11 in mouse. From E12, scgn+ cells commute towards the extended amygdala and colonize the bed nucleus of stria terminalis, the interstitial nucleus of the posterior limb of the anterior commissure, the dorsal substantia innominata (SI) and the central and medial amygdaloid nuclei. Scgn+ neurons can acquire a cholinergic phenotype in the SI or differentiate into GABA cells in the central amygdala. We also uncover phylogenetic differences in scgn expression as this CBP defines not only neurons destined to the extended amygdala but also cholinergic projection cells and cortical pyramidal cells in the fetal nonhuman primate and human brains, respectively. Overall, our findings emphasize the developmentally shared origins of neurons populating the extended amygdala, and suggest that secretagogin can be relevant to the generation of functional modalities in specific neuronal circuitries. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The combination of raltegravir, etravirine and ritonavir boosted darunavir is a potent antiretroviral regimen for patients who have been heavily pre-treated for HIV-infection. All these agents have to exert their action intracellularly. However, only little is known about the cellular pharmacology of these agents. WHAT THIS STUDY ADDS • We investigated the steady-state plasma and cellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir and the observed distinct intracellular accumulation ratios indicated that these antiretroviral drugs have different affinity for the cellular compartment. AIM To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. METHODS Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. RESULTS Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l−1 in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. CONCLUSIONS The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK-PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance. [ABSTRACT FROM AUTHOR]

In the early postnatal period, energy metabolism in the suckling rodent brain relies to a large extent on metabolic pathways alternate to glucose such as the utilization of ketone bodies (KBs). However, how KBs affect neuronal excitability is not known. Using recordings of single NMDA and GABA-activated channels in neocortical pyramidal cells we studied the effects of KBs on the resting membrane potential ( Em) and reversal potential of GABA-induced anionic currents ( EGABA), respectively. We show that during postnatal development (P3–P19) if neocortical brain slices are adequately supplied with KBs, Em and EGABA are both maintained at negative levels of about −83 and −80 mV, respectively. Conversely, a KB deficiency causes a significant depolarization of both Em (>5 mV) and EGABA (>15 mV). The KB-mediated shift in EGABA is largely determined by the interaction of the NKCC1 cotransporter and Cl−/HCO3 transporter(s). Therefore, by inducing a hyperpolarizing shift in Em and modulating GABA signaling mode, KBs can efficiently control the excitability of neonatal cortical neurons. [ABSTRACT FROM AUTHOR]

Objective: To review systematically the reported effects of platelet-rich plasma (PRP) on bone regeneration. Material and methods: Up to June 2006, MEDLINE and Cochrane databases were explored with different combinations of three search terms: ‘PRP’, ‘bone regeneration’, ‘dentistry’ and their synonyms. Inclusion criteria: human controlled clinical trials designed to treat maxillofacial bony defects with application of PRP (test) or without PRP (control), including at least five patients with a follow-up period of more than 3 months and using clinical assessment, radiography, histology and/or histomorphometry for evaluation. Literature search, selection of eligible articles and data extraction were carried out independently by two readers. Results: The literature search revealed 108 references, of which 17 were selected for further analysis. Finally, nine articles fulfilling the inclusion criteria were selected for systematically review. Owing the substantial heterogeneity of the studies it was not possible to analyze the data statistically. An attempt was made to compare results from studies that used similar outcome measures by calculating and adding confidence intervals to the data presented in the original papers. Differences in treatment effects for periodontal defects in terms of clinical attachment level (CAL) were significant (ranging from 0.8 to 3.2 mm). The reported effects of PRP in sinus elevation (compared with their controls) were <10%. Conclusion: We found evidence for beneficial effects of PRP in the treatment of periodontal defects. Evidence for beneficial effects of PRP in sinus elevation appeared to be weak. No conclusions can be drawn about other applications of PRP in dentistry. [ABSTRACT FROM AUTHOR]

Soil C dynamics below the plow layer have been little studied, in spite of proven large C stocks and suspected large C stabilization potential. The objective of the present study was to determine C-turnover kinetics throughout the 1-m profile of a cultivated loam soil of the Paris basin, France. The soil 13C signature was determined to depths of 1.05 m in 32 replicated plots having received from 0 to 10 yr of maize after wheat. Above- and below-ground maize-residue biomass inputs were estimated throughout the 10-yr period. After 10 yr, maize-derived soil organic carbon (SOC) constituted about 10, 5, and 2% of the total SOC at 15-, 50-, and 100-cm depths, respectively. About one-third of recently de- posited maize-derived SOM present in the 1-m soil profile was retrieved below the Ap horizon. The ratios of maize-derived soil C to the cumulative maize above, and below-ground inputs over the 10-yr period averaged 17% across the soil profile. This ratio was lower in the Ap horizon (i.e., 13%) than in deeper soil horizons. Circumstantial evidences suggest that the distribution profile of recently deposited maize- derived C was influenced by fine root activities, bioturbation, and dissolved organic carbon (DOC) transport, the latter being substantiated by a high correlation (r² 0.86) between SOC contents and amorphous Fe + Al contents. In conclusion, our study stresses the need to take into account the full 1-m soil profile in C sequestration studies. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the decision-making behavior of general dental practitioners (GDPs) in performing routine oral examinations (ROEs). Change over time was studied by comparing data from a cohort sample of participants in two surveys in 2000 and 2005. A written questionnaire was sent to 809 dentists (509 responses were obtained) and 475 (61%) were used for analysis. Of the respondents, 347 also participated in the survey in 2000. The mean number of diagnostic ROE items per ROE was 6.9 (standard deviation = 1.7). Groups of GDPs were distinguished based on their answer to the question ‘Do you apply for all patients a fixed recall interval between two successive ROEs?’ and four personal profiles. Of the GDPs, 38.5% ( n = 183) assigned fixed recall intervals (Fxs) for all patients. Individual recall intervals (Ivs) were applied by 61.5% ( n = 292) of GDPs, depending on specific selected patient characteristics and risk factors. Logistic regression showed that GDPs applying Fxs also used fixed periods between successive bitewing radiographs. Furthermore, GDPs applying Ivs conducted more frequent periodontal screening and, in the event of periodontal problems, were more inclined to prescribe radiographs. Over a 5 yr period, a shift towards Ivs assignment (from 49% in 2000 to 61.5% in 2005) was found. Differences in assigned recall intervals (Fxs/Ivs) by GDPs are determined by three clinical ROE predictors and two GDP profiles. A shift towards a more individual assessment was found between 2000 and 2005 in the way that Dutch GDPs are dealing with the assignment of recall interval frequency. [ABSTRACT FROM AUTHOR]

The excitability of dopaminergic (DA) neurons in the substantia nigra is controlled by the convergent activity of multiple glutamatergic afferents. Here, we show that vesicular glutamate transporter 3 (VGLUT3)-immunoreactive (ir) terminals segregate to the perisomatic region of DA neurons in the substantia nigra pars compacta, and VGLUT3 decorates a synapse population distinct from those marked by vesicular glutamate transporters 1 and 2. VGLUT3-ir nerve endings form asymmetric terminals on DA neurons. Retrograde tracing suggests the superior colliculus as an origin of excitatory VGLUT3-ir afferents. Collectively, our data indicate that VGLUT3 identifies a novel excitatory terminal subset that contributes to the tuning of DA cell excitability in the substantia nigra. [ABSTRACT FROM AUTHOR]

The objective of this study was twofold, namely to evaluate the effectiveness of a dental clinical practice guideline on the management of asymptomatic impacted lower third molars (i) on referral rates and (ii) on dentists' change in knowledge. A two-arm cluster randomized controlled trial, with pre- and post-test assessments, was conducted. A guideline was implemented by multifaceted interventions (i.e. feedback, reminders, and an interactive meeting). The effect was evaluated after 1 yr by repeating the baseline questionnaire and by monitoring the number of patients who were referred for removal of their asymptomatic impacted mandibular third molars. Instruments were questionnaires for detecting changes in knowledge, patient records, and panoramic radiographs. The knowledge of dentists regarding asymptomatic mandibular third molar management was found to increase significantly in the intervention group as compared to the control group. There was no statistically significant difference between the groups in guideline-consistent patient referral rates at the post-test assessment. It was concluded that the methodology employed for dissemination and implementation of a clinical practice guideline on asymptomatic mandibular third molar management improves dentists' knowledge on this topic and is effective in improving decision-making in simulated cases; however, no clinical effect was demonstrated. [ABSTRACT FROM AUTHOR]

The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir. HIV-1-infected patients being treated with an indinavir-containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM). The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h−1 (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h−1, respectively. An absorption lag-time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100–400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co-administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males. The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non-nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg. [ABSTRACT FROM AUTHOR]

Mettes TG, Bruers JJM, van der Sanden WJM, Verdonschot EH, Mulder J, Grol RPTM, Plasschaert AJM. Routine oral examination: differences in characteristics of Dutch general dental practitioners related to type of recall interval. Community Dent Oral Epidemiol 2005; 33: 219–26.© Blackwell Munksgaard, 2005The aim of this study was to explore differences in behaviour (characteristics and opinions) among general dental practitioners (GDPs), using either a fixed (Fx) or an individualized recall interval (Iv) between successive routine oral examinations (ROEs).In the year 2000, data were collected by means of a written questionnaire sent to a random stratified sample of 610 dentists of whom 521 responded, of which 508 (83%) were used for analysis.Two groups of GDPs were distinguished based on their answer to the question:‘Do you apply for all patients a fixed recall interval between two successive ROEs?’ Fifty-one per cent of the GDPs (n = 257) applied Fxs for all patients, generally for a period of 6 months. Ivs were applied by 49% (n = 251) of GDPs, depending on the determination of specific patient characteristics. Logistic regression analysis showed that GDPs applying Fxs also used fixed periods between successive bitewing radiographs for all patients. Furthermore, dentists applying Ivs required more time to conduct an ROE, partly because of a more extensive periodontal screening. GDPs applying Fxs, adhered more to the opinion that a fixed recall regime (every 6 months, as existed before 1995) should be re-introduced, whereas the GDPs in support of Ivs were more in favour to support the opinion that the ROE is‘an excellent instrument for effective, individualized oral care’.Dutch GDPs differ in the way they deal with the determination of recall interval frequency. These are also specific differences in performance and opinions regarding ROE. With the changing prevalence of oral diseases and the skewed distribution within populations, further research is advocated on consistent decision making to determine the most appropriate recall policy in preventing oral disease. [ABSTRACT FROM AUTHOR]

Presents the future of strategic environmental assessment (SEA) and sustainability in Europe. Requirements for SEA; Role of SEA in enhancing the integration of environmental policy integration and sustainable development; Contents of the SEA Directive.

The aim of this study was to develop and validate a population pharmacokinetic model of ritonavir, used as an antiviral agent or as a booster, in a large patient population and to identify factors influencing its pharmacokinetics.Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, the Netherlands, who were being treated with a ritonavir-containing regimen were included. During regular visits, blood samples were collected for the determination of ritonavir plasma concentrations and several clinical chemistry parameters. Furthermore, complete pharmacokinetic curves were available in some patients. Single and multiple compartment models with zero-order and first-order absorption, with and without absorption lag-time, with linear and nonlinear elimination were tested, using nonlinear mixed effect modelling (NONMEM). Pharmacokinetic parameters and interindividual, interoccasion and residual variability were estimated. In addition, the influence of several factors (e.g. patient characteristics, comedication) on the pharmacokinetics of ritonavir was explored.From 186 patients 505 ritonavir plasma concentrations at a single time-point and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations. In total 62% of the patients used ritonavir as a booster of their protease inhibitor containing antiretroviral regimen. First order absorption in combination with one-compartment disposition best described the pharmacokinetics of ritonavir. Clearance, volume of distribution and absorption rate constant were 10.5 l h−1 (95% prediction interval (95% PI) 9.38–11.7), 96.6 l (95% PI 67.2–121) and 0.871 h−1 (95% PI 0.429–1.47), respectively, with 38.3%, 80.0% and 169% interindividual variability, respectively. The interoccasion variability in the apparent bioavailability was 59.1%. The concomitant use of lopinavir resulted in a 2.7-fold increase in the clearance of ritonavir (P value < 0.001). No patients characteristics influenced the pharmacokinetics of ritonavir.The pharmacokinetic parameters of ritonavir were adequately described by our population pharmacokinetic model. Concomitant use of the protease inhibitor lopinavir strongly influenced the pharmacokinetics of ritonavir. The model has been validated and can be used for further investigation of the interaction between ritonavir and other protease inhibitors. [ABSTRACT FROM AUTHOR]

Environmental stimuli during the perinatal period can result in persistent individual differences in neural viability and cognitive functions. Earlier studies have shown that brief daily maternal separation and/or handling of rat pups during the first weeks of life reduces stress reactivity during adulthood and attenuates neuronal loss and cognitive decline during aging. In the present study we examined whether neonatal handling also affects the sensitivity of the adult brain to an acute neurotoxic insult. Postnatally handled and nonhandled control rats were left undisturbed from weaning onwards until the age of 11 months. At this age, the animals were subjected to a neurotoxic challenge by unilateral infusion of 60 m M of the glutamate analogue N-methyl- D-aspartate (NMDA) into the nucleus basalis magnocellularis (NBM). The brains were collected to measure cholinergic cell and fiber loss. In the nonlesioned side of the brain, cholinergic cell number in the NBM and fiber density in the cortex were not different between postnatally handled and control rats. However, in the lesioned hemisphere handled animals exhibited a significantly higher loss of choline-acetyltransferase-immunoreactive and acetylcholinesterase-positive fibers in the somatosensory cortex. The present results provide evidence for an enhanced vulnerability of postnatally handled rats to acute neurodegeneration in contrast to the previously reported attenuation of spontaneous aging-related neurodegenerative processes. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 463-472, 2004 [ABSTRACT FROM AUTHOR]