Long-term elevation of β-hydroxybutyrate in dairy cows through infusion: effects on feed intake, milk production, and metabolism.

Elevation of ketone bodies in dairy cows frequently occurs in early lactation, usually concomitantly with a lack of energy and glucose. The objective of this study was to induce an elevated plasma β-hydroxybutyrate (BHBA) concentration over 48 h in mid-lactating dairy cows (i.e., during a period of positive energy balance and normal glucose plasma concentrations). Effects of BHBA infusion on feed intake, metabolism, and performance were investigated. Thirteen cows were randomly assigned to 1 of 2 infusion groups, including an intravenous infusion with Na-dl-β-OH-butyrate (1.7 mol/L) to achieve a plasma concentration of 1.5 to 2.0 mmol/L of BHBA (HyperB; n=5), or an infusion of 0.9% saline solution (control; n=8). Blood was sampled before and hourly during the 48 h of infusion. In the liver, mRNA transcripts related to gluconeogenesis (pyruvate carboxylase, glucose 6-phosphatase, mitochondrial phosphoenolpyruvate carboxykinase), phosphofructokinase, pyruvate dehydrogenase complex, and fatty acid synthesis (acetyl-coenzyme A carboxylase, fatty acid synthase) were measured by real-time PCR. Glyceraldehyde-3-phosphate dehydrogenase and ubiquitin were used as housekeeping genes. Changes (difference between before and after 48-h infusion) during the infusion period were evaluated by ANOVA with treatment as fixed effect, and area under the curve of variables was calculated on the second day of experiment. The plasma BHBA concentration in HyperB cows was 1.74 ± 0.02 mmol/L (mean ± SE) compared with 0.59 ± 0.02 mmol/L for control cows. The change in feed intake, milk yield, and energy corrected milk did not differ between the 2 experimental groups. Infusion of BHBA reduced the plasma glucose concentration (3.47 ± 0.11 mmol/L) in HyperB compared with control cows (4.11 ± 0.08 mmol/L). Plasma glucagon concentration in HyperB was lower than the control group. All other variables measured in plasma were not affected by treatment. In the liver, changes in mRNA abundance for the selected genes were similar between 2 groups. Results demonstrate that intravenous infusion of BHBA decreased plasma glucose concentration in dairy cows, but this decrease could not be explained by alterations in insulin concentrations or key enzymes related to gluconeogenesis. Declined glucose concentration is likely functionally related to decreased plasma glucagon concentration.

Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory.

A number of studies have established a role for vascular endothelial growth factor (VEGF) in angiogenesis. Recent reports have shown that VEGF overexpression in the hippocampus improves learning and memory and is associated with enhanced neurogenesis. PTK787/ZK222584 (PTK/ZK) is a reported inhibitor of VEGFR signaling that is currently being tested for its effects on lung and colon cancer. However, the influence of this drug on cognition has not been examined. In the present study, we questioned if post-training administration of PTK/ZK influences hippocampus-dependent memory. When administered to rats immediately following massed training in the Morris water maze, PTK/ZK impaired spatial memory retention tested 48 h later. This impairment was evidenced by increased latency to the hidden platform and fewer platform crossings. However, this impairment was not associated with a change in neurogenesis during this time frame. PTK/ZK infusion did not reduce VEGFR or AKT phosphorylation, but increased the phosphorylation of ERK. These studies suggest that VEGFR inhibitors such as PTK/ZK may negatively influence cognition.

Long-Term and Seasonal Variations in CO2: Linkages to Catchment Alkalinity Generation

As atmospheric emissions of S have declined in the Northern Hemisphere, there has been an expectation of increased pH and alkalinity in streams believed to have been acidified by excess S and N. Many streams and lakes have not recovered. Evidence from East Bear Brook in Maine, USA and modelling with the groundwater acid-base model MAGIC (Cosby et al. 1985a,b) indicate that seasonal and yearly variations in soil PCO2 are adequate to enhance or even reverse acid-base (alkalinity) changes anticipated from modest decreases of SO4 in surface waters. Alkalinity is generated in the soil by exchange of H+ from dissociation of H2CO3, which in turn is derived from the dissolving of soil CO2. The variation in soil PCO2 produces an alkalinity variation of up to 15 mu eq L-1 in stream water. Detecting and relating increases in alkalinity to decreases in stream SO4 are significantly more difficult in the short term because of this effect. For example, modelled alkalinity recovery at Bear Brook due to a decline of 20 mu eq SO4 L-1 in soil solution is compensated by a decline from 0.4 to 0.2% for soil air PCO2. This compensation ability decays over time as base saturation declines. Variable PCO2 has less effect in more acidic soils. Short-term decreases of PCO2 below the long-term average value produce short-term decreases in alkalinity, whereas short-term increases in PCO2 produce shortterm alkalization. Trend analysis for detecting recovery of streams and lakes from acidification after reduced atmospheric emissions will require a longer monitoring period for statistical significance than previously appreciated.

Contrasting long-term records of biomass burning in wet and dry savannas of equatorial East Africa

Rainfall controls fire in tropical savanna ecosystems through impacting both the amount and flammability of plant biomass, and consequently, predicted changes in tropical precipitation over the next century are likely to have contrasting effects on the fire regimes of wet and dry savannas. We reconstructed the long-term dynamics of biomass burning in equatorial East Africa, using fossil charcoal particles from two well-dated lake-sediment records in western Uganda and central Kenya. We compared these high-resolution (5 years/sample) time series of biomass burning, spanning the last 3800 and 1200 years, with independent data on past hydroclimatic variability and vegetation dynamics. In western Uganda, a rapid (<100 years) and permanent increase in burning occurred around 2170 years ago, when climatic drying replaced semideciduous forest by wooded grassland. At the century time scale, biomass burning was inversely related to moisture balance for much of the next two millennia until ca. 1750 ad, when burning increased strongly despite regional climate becoming wetter. A sustained decrease in burning since the mid20th century reflects the intensified modern-day landscape conversion into cropland and plantations. In contrast, in semiarid central Kenya, biomass burning peaked at intermediate moisture-balance levels, whereas it was lower both during the wettest and driest multidecadal periods of the last 1200 years. Here, burning steadily increased since the mid20th century, presumably due to more frequent deliberate ignitions for bush clearing and cattle ranching. Both the observed historical trends and regional contrasts in biomass burning are consistent with spatial variability in fire regimes across the African savanna biome today. They demonstrate the strong dependence of East African fire regimes on both climatic moisture balance and vegetation, and the extent to which this dependence is now being overridden by anthropogenic activity.

Long-term relationships among pesticide applications, mobility, and soil erosion in a vineyard watershed

Agricultural pesticide use has increased worldwide during the last several decades, but the long-term fate, storage, and transfer dynamics of pesticides in a changing environment are poorly understood. Many pesticides have been progressively banned, but in numerous cases, these molecules are stable and may persist in soils, sediments, and ice. Many studies have addressed the question of their possible remobilization as a result of global change. In this article, we present a retro-observation approach based on lake sediment records to monitor micropollutants and to evaluate the long-term succession and diffuse transfer of herbicides, fungicides, and insecticide treatments in a vineyard catchment in France. The sediment allows for a reliable reconstruction of past pesticide use through time, validated by the historical introduction, use, and banning of these organic and inorganic pesticides in local vineyards. Our results also revealed how changes in these practices affect storage conditions and, consequently, the pesticides’ transfer dynamics. For example, the use of postemergence herbicides (glyphosate), which induce an increase in soil erosion, led to a release of a banned remnant pesticide (dichlorodiphenyltrichloro- ethane, DDT), which had been previously stored in vineyard soil, back into the environment. Management strategies of ecotoxico- logical risk would be well served by recognition of the diversity of compounds stored in various environmental sinks, such as agriculture soil, and their capability to become sources when environmental conditions change.

The role of human-induced fire and sweet chestnut (Castanea sativa Mill.) cultivation on the long-term landscape dynamics of the southern Swiss Alps

Changes in fire occurrence during the last decades in the southern Swiss Alps make knowledge on fire history essential to understand future evolution of the ecosystem composition and functioning. In this context, palaeoecology provides useful insights into processes operating at decadal-to-millennial time scales, such as the response of plant communities to intensified fire disturbances during periods of cultural change. We provide a high-resolution macroscopic charcoal and pollen series from Guèr, a well-dated peat sequence at mid-elevation (832 m.a.s.l.) in southern Switzerland, where the presence of local settlements is documented since the late Bronze Age and the Iron Age. Quantitative fire reconstruction shows that fire activity sharply increased from the Neolithic period (1–3 episodes/1000 year) to the late Bronze and Iron Age (7–9 episodes/1000 year), leading to extensive clearance of the former mixed deciduous forest (Alnus glutinosa, Betula, deciduous Quercus). The increase in anthropogenic pollen indicators (e.g. Cerealia-type, Plantago lanceolata) together with macroscopic charcoal suggests anthropogenic rather than climatic forcing as the main cause of the observed vegetation shift. Fire and controlled burning were extensively used during the late Roman Times and early Middle Ages to promote the introduction and establishment of chestnut (Castanea sativa) stands, which provided an important wood and food supply. Fire occurrence declined markedly (from 9 to 5–6 episodes/1000 year) during late Middle Ages because of fire suppression, biomass removal by human population, and landscape fragmentation. Land-abandonment during the last decades allowed forest to partly re-expand (mainly Alnus glutinosa, Betula) and fire frequency to increase.

Effects of short- and long-term variations in RLS severity on perceived health status - the COR-study.

In a cohort study among 2751 members (71.5% females) of the German and Swiss RLS patient organizations changes in restless legs syndrome (RLS) severity over time was assessed and the impact on quality of life, sleep quality and depressive symptoms was analysed. A standard set of scales (RLS severity scale IRLS, SF-36, Pittsburgh Sleep Quality Index and the Centre for Epidemiologic Studies Depression Scale) in mailed questionnaires was repeatedly used to assess RLS severity and health status over time and a 7-day diary once to assess short-term variations. A clinically relevant change of the RLS severity was defined by a change of at least 5 points on the IRLS scale. During 36 months follow-up minimal improvement of RLS severity between assessments was observed. Men consistently reported higher severity scores. RLS severity increased with age reaching a plateau in the age group 45-54 years. During 3 years 60.2% of the participants had no relevant (±5 points) change in RLS severity. RLS worsening was significantly related to an increase in depressive symptoms and a decrease in sleep quality and quality of life. The short-term variation showed distinctive circadian patterns with rhythm magnitudes strongly related to RLS severity. The majority of participants had a stable course of severe RLS over three years. An increase in RLS severity was accompanied by a small to moderate negative, a decrease by a small positive influence on quality of life, depressive symptoms and sleep quality.

Meta-Analysis of Long-Term Land Management Effect on Soil Organic Carbon (SOC) in Ethiopia

The role of Soil Organic Carbon (SOC) in mitigating climate change, indicating soil quality and ecosystem function has created research interested to know the nature of SOC at landscape level. The objective of this study was to examine variation and distribution of SOC in a long-term land management at a watershed and plot level. This study was based on meta-analysis of three case studies and 128 surface soil samples from Ethiopia. Three sites (Gununo, Anjeni and Maybar) were compared after considering two Land Management Categories (LMC) and three types of land uses (LUT) in quasi-experimental design. Shapiro-Wilk tests showed non-normal distribution (p = 0.002, a = 0.05) of the data. SOC median value showed the effect of long-term land management with values of 2.29 and 2.38 g kg-1 for less and better-managed watersheds, respectively. SOC values were 1.7, 2.8 and 2.6 g kg-1 for Crop (CLU), Grass (GLU) and Forest Land Use (FLU), respectively. The rank order for SOC variability was FLU>GLU>CLU. Mann-Whitney U and Kruskal-Wallis test showed a significant difference in the medians and distribution of SOC among the LUT, between soil profiles (p<0.05, confidence interval 95%, a = 0.05) while it is not significant (p>0.05) for LMC. The mean and sum rank of Mann Whitney U and Kruskal Wallis test also showed the difference at watershed and plot level. Using SOC as a predictor, cross-validated correct classification with discriminant analysis showed 46 and 49% for LUT and LMC, respectively. The study showed how to categorize landscapes using SOC with respect to land management for decision-makers.

Pre-therapy inflammation and coagulation activation and long-term CD4 count responses to the initiation of antiretroviral therapy

OBJECTIVES Pre-antiretroviral therapy (ART) inflammation and coagulation activation predict clinical outcomes in HIV-positive individuals. We assessed whether pre-ART inflammatory marker levels predicted the CD4 count response to ART. METHODS Analyses were based on data from the Strategic Management of Antiretroviral Therapy (SMART) trial, an international trial evaluating continuous vs. interrupted ART, and the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial, evaluating three first-line ART regimens with at least two drug classes. For this analysis, participants had to be ART-naïve or off ART at randomization and (re)starting ART and have C-reactive protein (CRP), interleukin-6 (IL-6) and D-dimer measured pre-ART. Using random effects linear models, we assessed the association between each of the biomarker levels, categorized as quartiles, and change in CD4 count from ART initiation to 24 months post-ART. Analyses adjusted for CD4 count at ART initiation (baseline), study arm, follow-up time and other known confounders. RESULTS Overall, 1084 individuals [659 from SMART (26% ART naïve) and 425 from FIRST] met the eligibility criteria, providing 8264 CD4 count measurements. Seventy-five per cent of individuals were male with the mean age of 42 years. The median (interquartile range) baseline CD4 counts were 416 (350-530) and 100 (22-300) cells/μL in SMART and FIRST, respectively. All of the biomarkers were inversely associated with baseline CD4 count in FIRST but not in SMART. In adjusted models, there was no clear relationship between changing biomarker levels and mean change in CD4 count post-ART (P for trend: CRP, P = 0.97; IL-6, P = 0.25; and D-dimer, P = 0.29). CONCLUSIONS Pre-ART inflammation and coagulation activation do not predict CD4 count response to ART and appear to influence the risk of clinical outcomes through other mechanisms than blunting long-term CD4 count gain.

The association between in-stent neoatherosclerosis and native coronary artery disease progression: a long-term angiographic and optical coherence tomography cohort study.

AIMS The purpose of the present study was to investigate the relationship between in-stent neoatherosclerosis (NA) and native atherosclerosis progression of untreated coronary segments. METHODS AND RESULTS In-stent NA was assessed by optical coherence tomography (OCT) among patients included in the SIRTAX-LATE OCT study 5 years after drug-eluting stent (DES) (sirolimus-eluting and paclitaxel-eluting stents) implantation. Neoatherosclerosis was defined as the presence of fibroatheroma or fibrocalcific plaque within the neointima of stented segments with a longitudinal extension >1.0 mm. Atherosclerosis progression in untreated native coronary segments was evaluated by serial quantitative coronary angiography (QCA). The change in minimal lumen diameter (MLD) was serially assessed within matched segments at baseline and 5-year angiographic follow-up. The key clinical endpoint was non-target lesion (non-TL) revascularization throughout 5 years. A total of 88 patients with 88 lesions were available for OCT analysis 5 years after DES implantation. In-stent NA was observed in 16% of lesions with the majority of plaques being fibroatheromas (11.4%) followed by fibrocalcific plaques (5.7%). A total of 704 non-TL segments were serially evaluated by QCA. Between baseline and 5-year follow-up, the reduction in MLD was significantly more pronounced in patients with NA (-0.25 mm, 95% CI -0.36 to -0.17 mm) when compared with patients without NA (-0.13 mm, 95% CI -0.17 to -0.10 mm, P = 0.002). Similarly, non-TL revascularization was more frequent in patients with NA (78.6%) when compared with patients without NA (44.6%, P = 0.028) throughout 5 years. CONCLUSIONS In-stent NA is more common among patients with angiographic and clinical evidence of native atherosclerosis progression suggesting similar pathophysiological mechanisms.SIRTAX trial is registered at http://www.clinicaltrials.gov/ct2/show/NCT00617084.

Long-term trends in invertebrate–habitat relationships under protected and fished conditions

Few studies examine the long-term effects of changing predator size and abundance on the habitat associations of resident organisms despite that this knowledge is critical to understand the ecosystem effects of fishing. Marine reserves offer the opportunity to determine ecosystem-level effects of manipulated predator densities, while parallel monitoring of adjacent fished areas allows separating these effects from regional-scale change. Relationships between two measures of benthic habitat structure (reef architecture and topographic complexity) and key invertebrate species were followed over 17 years at fished and protected subtidal rocky reefs associated with two southern Australian marine reserves. Two commercially harvested species, the southern rock lobster (Jasus edwardsii) and blacklip abalone (Haliotis rubra) were initially weakly associated with habitat structure across all fished and protected sites. The strength of association with habitat for both species increased markedly at protected sites 2 years after marine reserve declaration, and then gradually weakened over subsequent years. The increasing size of rock lobster within reserves apparently reduced their dependency on reef shelters as refuges from predation. Rising predation by fish and rock lobster in the reserves corresponded with weakening invertebrate–habitat relationships for H. rubra and sea urchins (Heliocidaris erythrogramma). These results emphasise that animal–habitat relationships are not necessarily stable through time and highlight the value of marine reserves as reference sites. Our work shows that fishery closures to enhance populations of commercially important and keystone species should be in areas with a range of habitat features to accommodate shifting ecological requirements with ontogenesis.

Long-term hydrological dynamics and fire history over the last 2000 years in CE Europe reconstructed from a high-resolution peat archive

Sphagnum peatlands in the oceanic-continental transition zone of Poland are currently influenced by climatic and anthropogenic factors that lead to peat desiccation and susceptibility to fire. Little is known about the response of Sphagnum peatland testate amoebae (TA) to the combined effects of drought and fire. To understand the relationships between hydrology and fire dynamics, we used high-resolution multi-proxy palaeoecological data to reconstruct 2000 years of mire history in northern Poland. We employed a new approach for Polish peatlands – joint TA-based water table depth and charcoal-inferred fire activity reconstructions. In addition, the response of most abundant TA hydrological indicators to charcoal-inferred fire activity was assessed. The results show four hydrological stages of peatland development: moderately wet (from ∼35 BC to 800 AD), wet (from ∼800 to 1390 AD), dry (from ∼1390 to 1700 AD) and with an instable water table (from ∼1700 to 2012 AD). Fire activity has increased in the last millennium after constant human presence in the mire surroundings. Higher fire activity caused a rise in the water table, but later an abrupt drought appeared at the onset of the Little Ice Age. This dry phase is characterized by high ash contents and high charcoal-inferred fire activity. Fires preceded hydrological change and the response of TA to fire was indirect. Peatland drying and hydrological instability was connected with TA community changes from wet (dominance of Archerella flavum, Hyalosphenia papilio, Amphitrema wrightianum) to dry (dominance of Cryptodifflugia oviformis, Euglypha rotunda); however, no clear fire indicator species was found. Anthropogenic activities can increase peat fires and cause substantial hydrology changes. Our data suggest that increased human fire activity was one of the main factors that influenced peatland hydrology, though the mire response through hydrological changes towards drier conditions was delayed in relation to the surrounding vegetation changes.

Trajectories of psychological adaptation to marital breakup after a long-term marriage

While the negative effects of divorce on well-being are well documented in research literature, the large individual differences in psychological adaptation over time are still not well understood. This is especially the case for marital breakup after long-term marriage, which is still a neglected research topic. Against this background, the aim of the present contribution is to shed light on the various trajectories of psychological adaptation to marital breakup after a long-term relationship. Data stem from a longitudinal survey study, which is part of the Swiss National Centre of Competence in Research ‘LIVES – Overcoming vulnerability: life course perspectives’ (funded by the Swiss National Science Foundation). Our analyses are based on results of an exploratory latent profile analysis performed at the first assessment in 2012 among 308 divorced participants aged 45 – 65 years, who divorced after an average of 25 years of marriage (Perrig-Chiello, Hutchison, & Morselli, 2014). Five different groups regarding psychological adaptation to marital breakup (i.e. life satisfaction, depression, hopelessness, subjective health, and mourning) were identified. They were composed of two larger groups of individuals that adapted quite well or very well (“average copers”, n=151 and “resilients”, n=90) and of three smaller groups with major difficulties to adjust to the new situation (“vulnerables”, n= 18; “malcontens”, n= 37 and “resigned ones”, n=12). Clusters differed statistically significant regarding personality variables, time since separation, current relationship status, and financial situation. In the present contribution, we want to investigate the course of adaptation of the five classes two years later by using latent transition analysis. Furthermore, we aim to examine which variables in terms of personality, relationship status, variables of the context of the separation and socio-demographic variables are crucial for change or stability in levels of adaptation in the different classes. The evaluation of the trajectories of adaptation to this critical life event and the identification of variables that enhance the adaptation over time is essential for developing more differentiated measures in counselling as well as intervention techniques in clinical and social services.

Trajectories of psychological adaptation to marital breakup after a long-term marriage

Background: Marital dissolution is known to be among the most stressful life events with long- reaching negative consequences on individuals’ lives. A limitation in research to date is that most studies have focused on the impact of marital disruption on well-being outcomes in younger adults. Furthermore, although population-based studies on divorce document a broad range of negative effects, more fine-grained analyses reveal a large heterogeneity in people’s adjustment, which is still not well understood. Objective: To explore trajectories of psychological adaptation to marital breakup after a long-term marriage, and to examine variables accounting for recovery or chronicity in terms of intrapersonal resources (personality, trait resilience, personal growth), relationship variables (satisfaction with ex- relationship, length of marriage, time since divorce) and socio-demographic variables (age, gender, financial situation). Methods: Latent transition analysis is used to examine the course of psychological adaptation (i.e., depressive symptoms, life satisfaction, hopelessness, mourning and subjective health) to divorce over two years among five profiles of 308 divorcees (mean age: 55.6 years; average duration of former marriage: 23.62 years): Two larger groups of individuals, the one which adapted very well (‘resilients’, 29%), the other quite well (‘average copers’, 49%), and three groups with major difficulties (‘vulnerables’, 6%; ‘malcontents’, 12%; and ‘resigned’, 4%). In a second step the differences among transition patterns were explored on the basis of the distal variables (i.e., intrapersonal resources, relationship variables, socio-demographics). Results: Although the probability of upward changes was higher for those individuals with lower adaptation at time 1, only a small number of individuals made an upward change from the maladapted to the well-adapted groups throughout the two years. The groups of copers and resilients remained stable in their psychological adaption. The most consistent results related to upward changes were intrapersonal resources, namely the NEO personality traits and trait resilience. Conclusion: The majority of individuals divorcing after a long-term marriage adapt successfully over time. Adaptation trajectories depend primarily on intrapersonal resources. However, a minority of divorcees exhibit enduring difficulties. Knowledge about the diversity of these trajectories of vulnerability could be of great help for designing psychological interventions to better tackle this critical life event.

Very long-term survival patterns of young patients treated with radical prostatectomy for high-risk prostate cancer

OBJECTIVE In patients with a long life expectancy with high-risk (HR) prostate cancer (PCa), the chance to die from PCa is not negligible and may change significantly according to the time elapsed from surgery. The aim of this study was to evaluate long-term survival patterns in young patients treated with radical prostatectomy (RP) for HRPCa. MATERIALS AND METHODS Within a multiinstitutional cohort, 600 young patients (≤59 years) treated with RP between 1987 and 2012 for HRPCa (defined as at least one of the following adverse characteristics: prostate specific antigen>20, cT3 or higher, biopsy Gleason sum 8-10) were identified. Smoothed cumulative incidence plot was performed to assess cancer-specific mortality (CSM) and other cause mortality (OCM) rates at 10, 15, and 20 years after RP. The same analyses were performed to assess the 5-year probability of CSM and OCM in patients who survived 5, 10, and 15 years after RP. A multivariable competing risk regression model was fitted to identify predictors of CSM and OCM. RESULTS The 10-, 15- and 20-year CSM and OCM rates were 11.6% and 5.5% vs. 15.5% and 13.5% vs. 18.4% and 19.3%, respectively. The 5-year probability of CSM and OCM rates among patients who survived at 5, 10, and 15 years after RP, were 6.4% and 2.7% vs. 4.6% and 9.6% vs. 4.2% and 8.2%, respectively. Year of surgery, pathological stage and Gleason score, surgical margin status and lymph node invasion were the major determinants of CSM (all P≤0.03). Conversely, none of the covariates was significantly associated with OCM (all P≥ 0.09). CONCLUSIONS Very long-term cancer control in young high-risk patients after RP is highly satisfactory. The probability of dying from PCa in young patients is the leading cause of death during the first 10 years of survivorship after RP. Thereafter, mortality not related to PCa became the main cause of death. Consequently, surgery should be consider among young patients with high-risk disease and strict PCa follow-up should enforce during the first 10 years of survivorship after RP.