Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

A major challenge in the emerging field of toxicogenomics is to define the relationships between chemically induced changes in gene expression and alterations in conventional toxicologic parameters such as clinical chemistry and histopathology. We have explored these relationships in detail using the rodent uterotrophic assay as a model system. Gene expression levels, uterine weights, and histologic parameters were analyzed 1, 2, 4, 8, 24, 48, and 72 hr after exposure to the reference physiologic estrogen 17β-estradiol (E(2)). A multistep analysis method, involving unsupervised hierarchical clustering followed by supervised gene ontology–driven clustering, was used to define the transcriptional program associated with E(2)-induced uterine growth and to identify groups of genes that may drive specific histologic changes in the uterus. This revealed that uterine growth and maturation are preceded and accompanied by a complex, multistage molecular program. The program begins with the induction of genes involved in transcriptional regulation and signal transduction and is followed, sequentially, by the regulation of genes involved in protein biosynthesis, cell proliferation, and epithelial cell differentiation. Furthermore, we have identified genes with common molecular functions that may drive fluid uptake, coordinated cell division, and remodeling of luminal epithelial cells. These data define the mechanism by which an estrogen induces organ growth and tissue maturation, and demonstrate that comparison of temporal changes in gene expression and conventional toxicology end points can facilitate the phenotypic anchoring of toxicogenomic data

Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy:Results of the EUROCONDOR Clinical Trial

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit

Medium Chain Acylcarnitines Dominate the Metabolite Pattern in Humans under Moderate Intensity Exercise and Support Lipid Oxidation

Background: Exercise is an extreme physiological challenge for skeletal muscle energy metabolism and has notable health benefits. We aimed to identify and characterize metabolites, which are components of the regulatory network mediating the beneficial metabolic adaptation to exercise

Biophysical aspects of handcycling performance in rehabilitation, daily life and recreational sports; a narrative review

Aim In this narrative review the potential and importance of handcycling are evaluated. Four conceptual models form the framework for this review; (1) the International Classification of Functioning, Disability and Health; (2) the Stress-Strain-Capacity model; (3) the Human-Activity-Assistive Technology model; and (4) the power balance model for cyclic exercise. Methods Based on international handcycle experience in (scientific) research and practice, evidence-based benefits of handcycling and optimization of handcycle settings are presented and discussed for rehabilitation, daily life and recreational sports. Results As the load can be distributed over the full 360° cycle in handcycling, peak stresses in the shoulder joint and upper body muscles reduce. Moreover, by handcycling regularly, the physical capacity can be improved. The potential of handcycling as an exercise mode for a healthy lifestyle should be recognized and advocated much more widely in rehabilitation and adapted sports practice. The interface between handcycle and its user should be optimized by choosing a suitable person-specific handcycle, but mainly by optimizing the handcycle dimensions to one’s needs and desires. These dimensions can influence efficient handcycle use and potentially improve both endurance and speed of handcycling. Conclusion To optimize performance in rehabilitation, daily life and recreational sports, continued and more systematic research is required. Implications for rehabilitation Handcycling allows users to travel farther distances at higher speeds and to train outdoors. It should be recognized as an alternative exercise modality for daily outdoor use, also already in early rehabilitation, while it contributes to a healthy lifestyle. To individualize handcycle performance, the user-handcycle (assistive device) interface as well as the vehicle mechanics should be optimized to minimize external power and reduce friction, so that the upper body capacity can be efficiently used. To optimize handcycling individual performance, both the physiological and biomechanical aspects of handcycling should be considered when monitoring or testing handcycle exercise

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Availability of phosphorus to nursery plants

Lopez-Bucio et al. emphasises the importance of phosphorus (P) in world agricultural production. They state that it is one of the most important nutrients limiting agriculture. In acid and alkaline soils, which make up over 70% of the world's arable land, P forms insoluble compounds that are not available for plant use. To reduce P deficiencies and ensure plant productivity, nearly 30 million tons of P fertiliser are applied every year. Up to 80% ofthe applied fertiliser is lost because it becomes immobile and unavailable for plant uptake. The production of plants in nurseries in Australia, South Africa, and New Zealand has a history of difficulties related to P nutrition. This is because these countries often have soils that are inherently low in available P and native flora is adapted to this. Often when these types of plants are grown with fertilisers containing P, they have a relatively high proportion of plants that are prone to P toxicity, particularly the Australian and South African floras. In New Zealand this may have been compounded by an agricultural nation which has grown up with the need to regularly apply superphosphate to the land, and in fact aerial topdressing was developed in this part of the world. This paper seeks to review the availability of P in soils and container mixes so that an improved understanding will aid the P fertilisation of nursery plants