Success in restoring native plant communities on kimberlite mining dumps in the Afro-alpine Drakensberg region of Lesotho.

Rehabilitation strategies for degraded mine dumps have generally seen limited success due to different complications associated with mining biophysical disturbance. In this study, we tested a combination of two methods to expedite revegetation of kimberlite tailings at Letseng Diamond Mine (i.e., in the Afro-alpine areas of Lesotho). We ran trials on different growth media located on fine and coarse kimberlite tailings (i.e. sites) mixed with different substrate combinations and topsoil and sowing a seed mix comprised of native plant species. Overall, as predicted, fine kimberlite tailings displayed significantly higher plant abundance than coarse kimberlite tailings, and sown seeds performed significantly better than spontaneous colonisation by emerging species. Kimberlite tailings mixed with topsoil (100 mm) showed significantly greater plant abundance, and similarly, when coarse kimberlite tailings were introduced to fine tailings. Physicochemical analyses of growth media components suggested that topsoil provided additional nutrients and that plants could readily access available nutrients in the fine kimberlite tailings. We noted a gradual significant increase in plant abundance over 5 years, enhanced by new plant species emerging from the topsoil seed bank or by natural seed dispersal. Although plant abundance differed significantly, both fine and coarse kimberlite tailings displayed high plant species diversity (H = 3.4 and D = 0.95 and H = 3.5 and D = 0.95, respectively). Out of 36 emerging plant species, 15 species spontaneously colonised both growth media. The significant variation in abundance among plant species between treatments was mostly attributed to dominant forb species, namely Chrysocoma ciliata, Glumicalyx montanus, Oxalis obliquifolia, Senecio inaequidens and Trifolium burchellianum. We have identified suitable growth media for plant community restoration on kimberlite tailings in the Drakensberg alpine area using a seed mix of native plant species in combination with natural seed dispersal from the surrounding pristine environment. We provide evidence for using two complementary approaches to optimise native plant community development during restoration in the Drakensberg alpine area.

Online physiotherapy for people with axial spondyloarthritis: quantitative and qualitative data from a cohort study.

Life-long exercise is essential in axial spondyloarthritis (axSpA) management; however, long-term adherence is challenging. Online exercise programmes are an alternative to face-to-face physiotherapy. (1) To measure adherence to a 12-month, individualised, online physiotherapy programme for people with axSpA, and investigate the effects on disease activity, spinal mobility, work ability, quality of life and function. (2) To investigate associations between programme adherence and outcomes. (3) To explore participants' views of the programme and factors affecting adherence. Participants were 'non-exercisers' recruited from rheumatology outpatient services. Adherence was measured using online diary entries. Outcomes included the BATH indices, health status (EQ5D), Ankylosing Spondylitis Quality of Life (ASQOL), exercise capacity (6MWT), Work, Productivity and Activity Impairment in AS (WPAI), Exercise Attitude Questionnaire (EAQ) and Exercise Motivations Inventory-2 (EMI-2) at baseline, 6 and 12 months. Interviews determined views on the intervention and factors affecting adherence. Fifty participants were recruited. Over the 52-week intervention, adherence (five times/week) ranged from 19% (± 30%) to 44% (± 35%). Significant improvements were found in disease activity (BASDAI), spinal mobility (BASMI), 6MWT, AsQoL and EQ5D-VAS at 6 and 12 months. There were no associations between adherence and baseline variables or demographics. Interviews suggested support from others, routine, and feeling the benefit positively affected adherence. Conversely, lack of motivation, life events and symptoms negatively affected adherence. A 12-month online physiotherapy programme significantly improved symptoms in people with axSpA who were not regular exercisers. Adherence reduced over the intervention period. Online exercise programmes may benefit people with axSpA; however, strategies to improve adherence are required.

The Influence of Serpentine Soil on the Early Development of a Non-Serpentine African Thistle, Berkheya radula (Harv.) De Wild.

Serpentine soils are rich in heavy metals and poor in nutrients, limiting plant species' performance and survival. Nevertheless, specificities of such limitations as well as adaptability features required for thriving in serpentine environments are barely known. The Barberton Greenstone Belt in South Africa is an example of an area containing serpentine soil with adapted vegetation. In this study, a pot experiment was performed to compare development features (i.e., germination rates, leaf count, leaf length, biomass and photosynthetic capacity) during the early development of the non-serpentine species Berkheya radula, a genus consisting of known metal hyperaccumulators from serpentine areas in South Africa. B. radula was grown in serpentine soils taken from the Barberton region. B. radula leaves had heavy metals in concentrations that confirmed the species as a phytoextractor. There were trends for enhanced productivity and photosynthesis in the serpentine treatments compared to the control. Leaf count, leaf length, electron transport efficiency (ψEo/(1 - ψEo), density of reaction centers and PIABS,total were significantly and positively correlated with at least one of the heavy metals in the leaves. Germination rates were positively influenced by K, whereas biomass and the density of reaction centers were negatively affected by Ca and P, and only Ca, respectively. The heavy metals Zn, Ni and Co were positively correlated with each other, whereas they were negatively correlated with the macronutrients K, Ca and P. The latter correlated positively with each other, confirming higher fertility of the control soil. Our study suggests that B. radula exhibits metallophyte characteristics (i.e., preadapted), despite not naturally occurring on metal-enriched soil, and this provides evidence that the potential for bioaccumulation and phytoremediation is shared between serpentine and non-serpentine species in this genus.

Influence of land use and topography on distribution and bioaccumulation of potentially toxic metals in soil and plant leaves: A case study from Sekhukhuneland, South Africa.

Potentially toxic metal (PTM) enrichment of the soil-plant system in ultramafic and mining regions is a global concern as it affects the food chain. With expanding mining industry, it is important to assess if anthropogenic factors (i.e., land use practices) have a greater influence in this regard compared to natural factors (i.e., topography). Localities in Sekhukhuneland, South Africa, were selected along an altitudinal gradient (i.e., topography: upper slope, footslope, valley and valley bottom) and a land use profile (i.e., rangelands, gardens, tailings and wastelands) to investigate the distribution of Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, Sr and Zn of natural (i.e., ultramafic geology) and anthropogenic (i.e., mining) origin in surface soil and plant leaf tissue. Plant life form was considered as an additional factor to evaluate PTM accumulation in leaves. Findings revealed a wider distribution range for Cr and Ni in the surface soil. Co, Cu, Mg, Mo, Sr and Zn were accumulated (bioaccumulation factor, BAF > 1) in leaf tissue of 74% of the evaluated plants of which 83% were indigenous. Grasses, forbs, dwarf shrubs and shrubs showed the highest accumulation levels. Despite an observed trend in the distribution of PTMs in soils and plant leaves along the altitudinal gradient, no significant differences were determined among the topographic positions. Land use practices, however, differed significantly indicating anthropogenic interference as a predominant determinant of PTM enrichment of soil-plant systems. Metal tolerant dominant plants in Sekhukhuneland could be classified as metallophytes. Indigenous species, accumulators and excluders, showed prospects for phytoremediation and rehabilitation of metal contaminated sites, respectively. Concentrations of Cr and Co in food and medicinal plant leaves exceeded the international permissible limits, which highlighted the necessity to estimate human health risks for PTMs in metalliferous sites.

TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis.

BACKGROUND: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design. METHODS: A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways. DISCUSSION: TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation. TRIAL REGISTRATION: Trials Registration: ISRCTN, ISRCTN36667085 . Registered on September 26, 2014.

Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease-associated psychological morbidity.

BACKGROUND: Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8+ NKG2D+ T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood. OBJECTIVES: To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression. METHODS: We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort. RESULTS: Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression. CONCLUSIONS: Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D+ CD8+ T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood. AA is associated with changes in levels of interleukin (IL)-6, tumour necrosis factor-α, IL-1ß and type 17 cytokines. Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25), in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F. Levels of IL-17E and IL-22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17- and type 2 immune pathways. Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17- and type 2 immune dysregulation, rather than focusing narrowly on the CD8+ T-cell response. An immunological mechanism might contribute directly to the depression observed in people with AA.

Voluntary sustainability standards could significantly reduce detrimental impacts of global agriculture.

Voluntary sustainability standards (VSS) are stakeholder-derived principles with measurable and enforceable criteria to promote sustainable production outcomes. While institutional commitments to use VSS to meet sustainable procurement policies have grown rapidly over the past decade, we still have relatively little understanding of the (i) direct environmental benefits of large-scale VSS adoption; (ii) potential perverse indirect impacts of adoption; and (iii) implementation pathways. Here, we illustrate and address these knowledge gaps using an ecosystem service modeling and scenario analysis of Bonsucro, the leading VSS for sugarcane. We find that global compliance with the Bonsucro environmental standards would reduce current sugarcane production area (-24%), net tonnage (-11%), irrigation water use (-65%), nutrient loading (-34%), and greenhouse gas emissions from cultivation (-51%). Under a scenario of doubled global sugarcane production, Bonsucro adoption would further limit water use and greenhouse gas emissions by preventing sugarcane expansion into water-stressed and high-carbon stock ecosystems. This outcome was achieved via expansion largely on existing agricultural lands. However, displacement of other crops could drive detrimental impacts from indirect land use. We find that over half of the potential direct environmental benefits of Bonsucro standards under the doubling scenario could be achieved by targeting adoption in just 10% of global sugarcane production areas. However, designing policy that generates the most environmentally beneficial Bonsucro adoption pathway requires a better understanding of the economic and social costs of VSS adoption. Finally, we suggest research directions to advance sustainable consumption and production.

Level of adherence to prescribed exercise in spondyloarthritis and factors affecting this adherence: a systematic review.

Adherence is a primary determinant of the effectiveness of any intervention. Exercise is considered essential in the management of spondyloarthritis (SpA); however, the overall adherence to exercise programmes and factors affecting adherence are unknown. The aim of this systematic review was to examine measures of, and factors influencing adherence to, prescribed exercise programmes in people with SpA. A search was performed in August 2018 using five data bases; the Cochrane library, CINAHL, EMBASE, MEDLINE, and Web of Science Collections. Inclusion criteria were: studies with adults (> 18 years) with SpA, with a prescribed exercise intervention or educational programme with the aim of increasing exercise participation. Article quality was independently assessed by two assessors. Extracted descriptive data included: populations, interventions, measures of adherence and factors affecting adherence. Percentage adherence rates to prescribed exercises were calculated if not reported. Nine studies were included with a total of 658 participants, 95% of participants had a diagnosis of ankylosing spondylitis. Interventions and measurement of adherence varied, making comparisons difficult. Rates of adherence ranged from 51.4 to 95%. Single studies identified; adherence improved following educational programmes, and higher disease severity and longer diagnostic delays were associated with higher adherence. Conflicting evidence was found as to whether supervision of exercise improved adherence. Three consecutive studies demonstrated adherence reduced over time. Adherence to prescribed exercise in SpA was poorly reported and predominately for people with AS. The levels of adherence and factors affecting prescribed exercise in SpA remain unclear. Future research should measure adherence across a longer time period and investigate possible factors which may influence adherence.

The role of the immune system in kidney disease.

The immune system and the kidneys are closely linked. In health the kidneys contribute to immune homeostasis, while components of the immune system mediate many acute forms of renal disease and play a central role in progression of chronic kidney disease. A dysregulated immune system can have either direct or indirect renal effects. Direct immune-mediated kidney diseases are usually a consequence of autoantibodies directed against a constituent renal antigen, such as collagen IV in anti-glomerular basement membrane disease. Indirect immune-mediated renal disease often follows systemic autoimmunity with immune complex formation, but can also be due to uncontrolled activation of the complement pathways. Although the range of mechanisms of immune dysregulation leading to renal disease is broad, the pathways leading to injury are similar. Loss of immune homeostasis in renal disease results in perpetual immune cell recruitment and worsening damage to the kidney. Uncoordinated attempts at tissue repair, after immune-mediated disease or non-immune mediated injury, result in fibrosis of structures important for renal function, leading eventually to kidney failure. As renal disease often manifests clinically only when substantial damage has already occurred, new diagnostic methods and indeed treatments must be identified to inhibit further progression and promote appropriate tissue repair. Studying cases in which immune homeostasis is re-established may reveal new treatment possibilities.

The world's road to water scarcity: shortage and stress in the 20th century and pathways towards sustainability.

Water scarcity is a rapidly growing concern around the globe, but little is known about how it has developed over time. This study provides a first assessment of continuous sub-national trajectories of blue water consumption, renewable freshwater availability, and water scarcity for the entire 20th century. Water scarcity is analysed using the fundamental concepts of shortage (impacts due to low availability per capita) and stress (impacts due to high consumption relative to availability) which indicate difficulties in satisfying the needs of a population and overuse of resources respectively. While water consumption increased fourfold within the study period, the population under water scarcity increased from 0.24 billion (14% of global population) in the 1900s to 3.8 billion (58%) in the 2000s. Nearly all sub-national trajectories show an increasing trend in water scarcity. The concept of scarcity trajectory archetypes and shapes is introduced to characterize the historical development of water scarcity and suggest measures for alleviating water scarcity and increasing sustainability. Linking the scarcity trajectories to other datasets may help further deepen understanding of how trajectories relate to historical and future drivers, and hence help tackle these evolving challenges.

Web-based physiotherapy for people with axial spondyloarthritis (WEBPASS) - a study protocol.

BACKGROUND: Evidence suggests people with axial spondyloarthritis (axial SpA) should exercise up to five times per week but lack of time, symptoms, cost and distance are barriers to regular exercise in axial SpA. Personalised exercise programmes delivered via the internet might support people with axial SpA to reach these exercise targets. The aim of this study is to investigate the effect of, and adherence to, a 12 month personalised web-based physiotherapy programme for people with axial SpA. METHODS: Fifty people with axial SpA will be recruited to this prospective, interventional cohort study. Each participant will be assessed by a physiotherapist and an individualised exercise programme set up on www.webbasedphysio.com . Participants will be asked to complete their programme five times per week for 12 months. With the exception of adherence, data will be collected at baseline, 6 and 12 months. DISCUSSION: The primary outcome measure is adherence to the exercise programme over each four week cycle (20 sessions maximum per cycle) and over the 12 months. Secondary measures include function (BASFI), disease activity (BASDAI), work impairment (WPAI:SpA), quality of life (ASQoL, EQ5D), attitude to exercise (EMI-2, EAQ), spinal mobility (BASMI), physical activity and the six minute walk test. Participants will also be interviewed to explore their adherence, or otherwise, to the intervention. This study will determine the adherence and key clinical outcomes of a targeted web-based physiotherapy programme for axial SpA. This data will inform clinical practice and the development and implementation of similar programmes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02666313 , 20th January 2016.

Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases.

Protein kinases mediate protein phosphorylation, which is a fundamental component of cell signalling, with crucial roles in most signal transduction cascades: from controlling cell growth and proliferation to the initiation and regulation of immunological responses. Aberrant kinase activity is implicated in an increasing number of diseases, with more than 400 human diseases now linked either directly or indirectly to protein kinases. Protein kinases are therefore regarded as highly important drug targets, and are the subject of intensive research activity. The success of small molecule kinase inhibitors in the treatment of cancer, coupled with a greater understanding of inflammatory signalling cascades, has led to kinase inhibitors taking centre stage in the pursuit for new anti-inflammatory agents for the treatment of immune-mediated diseases. Herein we discuss the main classes of kinase inhibitors; namely Janus kinase (JAK), mitogen-activated protein kinase (MAPK) and spleen tyrosine kinase (Syk) inhibitors. We provide a mechanistic insight into how these inhibitors interfere with kinase signalling pathways and discuss the clinical successes and failures in the implementation of kinase-directed therapeutics in the context of inflammatory and autoimmune disorders.

[The PRISCUS list in clinical routine. Practicability and comparison to international PIM lists]. / Die PRISCUS-Liste im klinischen Test. Praktikabilität und Vergleich mit internationalen PIM-Listen.

BACKGROUND: Certain drugs are classified as potentially inappropriate medications (PIM) for the elderly. In 2010, the PRISCUS list was published, specifically designed for its applicability in the German pharmaceutical market. The aim of this study was to evaluate the PRISCUS list compared to international PIM lists. METHODS: Based on selected PIM lists (PRISCUS, STOPP/START, Beers), the medications of 308 patients at a clinic of geriatric rehabilitation were screened for PIMs. Applying START criteria, omission of indicated drug therapies was detected. RESULTS: Regarding the rate of PIM detection, the PRISCUS list was less sensitive than the application of STOPP criteria. While hospitalized, the mean number of administered PIMs per patient was 1.2 based on STOPP criteria and 0.5 based on the PRISCUS list. The lowest number of PIMs per patient was detected by applying the Beers list (0.4 PIMs). CONCLUSION: The Beers list should not be used in the German pharmaceutical market. The amendment of diagnosis-related STOPP criteria to the PRISCUS list would be useful to significantly advance therapeutic success and drug safety in the elderly.

Lost food, wasted resources: global food supply chain losses and their impacts on freshwater, cropland, and fertiliser use.

Reducing food losses and waste is considered to be one of the most promising measures to improve food security in the coming decades. Food losses also affect our use of resources, such as freshwater, cropland, and fertilisers. In this paper we estimate the global food supply losses due to lost and wasted food crops, and the resources used to produce them. We also quantify the potential food supply and resource savings that could be made by reducing food losses and waste. We used publically available global databases to conduct the study at the country level. We found that around one quarter of the produced food supply (614 kcal/cap/day) is lost within the food supply chain (FSC). The production of these lost and wasted food crops accounts for 24% of total freshwater resources used in food crop production (27 m(3)/cap/yr), 23% of total global cropland area (31 × 10(-3)ha/cap/yr), and 23% of total global fertiliser use (4.3 kg/cap/yr). The per capita use of resources for food losses is largest in North Africa & West-Central Asia (freshwater and cropland) and North America & Oceania (fertilisers). The smallest per capita use of resources for food losses is found in Sub-Saharan Africa (freshwater and fertilisers) and in Industrialised Asia (cropland). Relative to total food production, the smallest food supply and resource losses occur in South & Southeast Asia. If the lowest loss and waste percentages achieved in any region in each step of the FSC could be reached globally, food supply losses could be halved. By doing this, there would be enough food for approximately one billion extra people. Reducing the food losses and waste would thus be an important step towards increased food security, and would also increase the efficiency of resource use in food production.

Changes in time of sowing, flowering and maturity of cereals in Europe under climate change.

The phenological development of cereal crops from emergence through flowering to maturity is largely controlled by temperature, but also affected by day length and potential physiological stresses. Responses may vary between species and varieties. Climate change will affect the timing of cereal crop development, but exact changes will also depend on changes in varieties as affected by plant breeding and variety choices. This study aimed to assess changes in timing of major phenological stages of cereal crops in Northern and Central Europe under climate change. Records on dates of sowing, flowering, and maturity of wheat, oats and maize were collected from field experiments conducted during the period 1985-2009. Data for spring wheat and spring oats covered latitudes from 46 to 64°N, winter wheat from 46 to 61°N, and maize from 47 to 58°N. The number of observations (site-year-variety combinations) varied with phenological phase, but exceeded 2190, 227, 2076 and 1506 for winter wheat, spring wheat, spring oats and maize, respectively. The data were used to fit simple crop development models, assuming that the duration of the period until flowering depends on temperature and day length for wheat and oats, and on temperature for maize, and that the duration of the period from flowering to maturity in all species depends on temperature only. Species-specific base temperatures were used. Sowing date of spring cereals was estimated using a threshold temperature for the mean air temperature during 10 days prior to sowing. The mean estimated temperature thresholds for sowing were 6.1, 7.1 and 10.1°C for oats, wheat and maize, respectively. For spring oats and wheat the temperature threshold increased with latitude. The effective temperature sums required for both flowering and maturity increased with increasing mean annual temperature of the location, indicating that varieties are well adapted to given conditions. The responses of wheat and oats were largest for the period from flowering to maturity. Changes in timing of cereal phenology by 2040 were assessed for two climate model projections according to the observed dependencies on temperature and day length. The results showed advancements of sowing date of spring cereals by 1-3 weeks depending on climate model and region within Europe. The changes were largest in Northern Europe. Timing of flowering and maturity were projected to advance by 1-3 weeks. The changes were largest for grain maize and smallest for winter wheat, and they were generally largest in the western and northern part of the domain. There were considerable differences in predicted timing of sowing, flowering and maturity between the two climate model projections applied.

Shifts in comparative advantages for maize, oat and wheat cropping under climate change in Europe.

Climate change is anticipated to affect European agriculture, including the risk of emerging or re-emerging feed and food hazards. Indirectly, climate change may influence such hazards (e.g. the occurrence of mycotoxins) due to geographic shifts in the distribution of major cereal cropping systems and the consequences this may have for crop rotations. This paper analyses the impact of climate on cropping shares of maize, oat and wheat on a 50-km square grid across Europe (45-65°N) and provides model-based estimates of the changes in cropping shares in response to changes in temperature and precipitation as projected for the time period around 2040 by two regional climate models (RCM) with a moderate and a strong climate change signal, respectively. The projected cropping shares are based on the output from the two RCMs and on algorithms derived for the relation between meteorological data and observed cropping shares of maize, oat and wheat. The observed cropping shares show a south-to-north gradient, where maize had its maximum at 45-55°N, oat had its maximum at 55-65°N, and wheat was more evenly distributed along the latitudes in Europe. Under the projected climate changes, there was a general increase in maize cropping shares, whereas for oat no areas showed distinct increases. For wheat, the projected changes indicated a tendency towards higher cropping shares in the northern parts and lower cropping shares in the southern parts of the study area. The present modelling approach represents a simplification of factors determining the distribution of cereal crops, and also some uncertainties in the data basis were apparent. A promising way of future model improvement could be through a systematic analysis and inclusion of other variables, such as key soil properties and socio-economic conditions, influencing the comparative advantages of specific crops.

Neither mycophenolate acyl-glucuronide levels nor their areas under the curve are responsible for the gastrointestinal side effects in kidney transplant recipients receiving EC-MPA: a prospective trial.

INTRODUCTION: Since previous in vitro studies suspected the metabolite mycophenolate acyl-glucuronide (AcMPAG) to be responsible for the gastrointestinal side effects, we examined the correlation between AcMPAG blood levels and patient gastrointestinal satisfaction inquiries using a standardized, validated questionnaire. PATIENTS AND METHODS: We enrolled 63 renal transplant patients, however, two discontinued the study and 16 were excluded because of inadequate completion of the questionnaires or missing blood values or discontinuation of enteric coated mycophenolic acid (EC-MPA) therapy, severe side effects or viral infections. The final responses of 45 people were subjects to statistical analysis. Gastrointestinal side effects were examined using the Gastrointestinal Symptom Rating Scale (GSRS) completed at three times: T1 (3-5 days after transplantation), T2 (10-15 days), and T3 (3 months). The GSRS results generated two groups of patients based on cutoff values set at a score of 4 points for each item. Scores less than 4 were assumed to be "no side effects"; ≥4, "side effects." AcMPAG was measured by mass spectroscopy on blood samples obtained at fixed times generating three pharmacokinetic profiles per patient. RESULTS: There was no relation between high AcMPAG blood concentrations and gastrointestinal dissatisfaction. Neither Ac-MPAG area under the curve (AUC) in the absorption phase nor AcMPAG peak values correlated with gastrointestinal dissatisfaction. CONCLUSION: There was no significant correlation between mean AcMPAG and GSRS scores, although previous studies had suggested AcMPAG maximum values or alternatively AcMPAG AUC in the absorption phase to relate to side effects.