Neurodegeneration in diabetic retinopathy : does it really matter?

Altres ajuts: RS is supported by the following grants: Ministerio de Economía y Competitividad and the Fundació Marató TV3 (201629-10). AWS is supported by the following grants: Fight for Sight, The Belfast Association for the Blind and The Jules Thorn Trust. TWG is supported by the following grants: R01EY20582, R24DK082841, Research to Prevent Blindness and The Taubman Medical Research Institute.The concept of diabetic retinopathy as a microvascular disease has evolved, in that it is now considered a more complex diabetic complication in which neurodegeneration plays a significant role. In this article we provide a critical overview of the role of microvascular abnormalities and neurodegeneration in the pathogenesis of diabetic retinopathy. A special emphasis is placed on the pathophysiology of the neurovascular unit (NVU), including the contributions of microvascular and neural elements. The potential mechanisms linking retinal neurodegeneration and early microvascular impairment, and the effects of neuroprotective drugs are summarised. Additionally, we discuss how the assessment of retinal neurodegeneration could be an important index of cognitive status, thus helping to identify individuals at risk of dementia, which will impact on current procedures for diabetes management. We conclude that glial, neural and microvascular dysfunction are interdependent and essential for the development of diabetic retinopathy. Despite this intricate relationship, retinal neurodegeneration is a critical endpoint and neuroprotection, itself, can be considered a therapeutic target, independently of its potential impact on microvascular disease. In addition, interventional studies targeting pathogenic pathways that impact the NVU are needed. Findings from these studies will be crucial, not only for increasing our understanding of diabetic retinopathy, but also to help to implement a timely and efficient personalised medicine approach for treating this diabetic complication

A kinetic analysis methodology to elucidate the roles of metal, support and solvent for the hydrogenation of 4-phenyl-2-butanone over Pt/TiO<inf>2</inf>

The rate and, more importantly, selectivity (ketone vs aromatic ring) of the hydrogenation of 4-phenyl-2-butanone over a Pt/TiO₂ catalyst have been shown to vary with solvent. In this study, a fundamental kinetic model for this multi-phase reaction has been developed incorporating statistical analysis methods to strengthen the foundations of mechanistically sound kinetic models. A 2-site model was determined to be most appropriate, describing aromatic hydrogenation (postulated to be over a platinum site) and ketone hydrogenation (postulated to be at the platinum–titania interface). Solvent choice has little impact on the ketone hydrogenation rate constant but strongly impacts aromatic hydrogenation due to solvent-catalyst interaction. Reaction selectivity is also correlated to a fitted product adsorption constant parameter. The kinetic analysis method shown has demonstrated the role of solvents in influencing reactant adsorption and reaction selectivity.We acknowledge EPSRC for funding as part of the CASTech grant (EP/G011397/1) and the Department of Employment and Learning for a studentship (IM). NSB was funded by a PhD scholarship from the University of Birmingham. SKW was supported by an Engineering Doctorate Studentship in Formulation Engineering at the University of Birmingham sponsored by the EPSRC (EP/G036713/1) and Johnson Matthey.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.jcat.2015.06.00

Effect of solvent on the hydrogenation of 4-phenyl-2-butanone over Pt based catalysts

In part I of this study, experimental data were presented for the hydrogenation of 4-phenyl-2-butanone with a 4% Pt/TiO2 catalyst where the reaction rate and selectivity (ketone vs. aromatic ring) varied with solvent. In this paper, a rigorous kinetic model is presented utilising these data, incorporating statistical analysis methods to strengthen the foundations of mechanistically sound kinetic models. A fundamental kinetic model for the system is presented and a 2-site model was determined to be most appropriate, describing aromatic hydrogenation (postulated to be over a platinum site) and ketone hydrogenation (at the platinum titania interface). Solvent choice has little impact on the ketone hydrogenation rate constant but strongly impacts aromatic hydrogenation due to solvent-catalyst interaction. Reaction selectivity is also correlated to a fitted product adsorption constant parameter. This kinetic analysis method is the first of its kind demonstrating the role of solvents in influencing reactant adsorption and reaction selectivity.We acknowledge EPSRC for funding as part of the CASTech grant (EP/G011397/1) and the Department of Employment and Learning for a studentship (IM). NSB was funded by a PhD scholarship from the University of Birmingham. SKW was supported by an Engineering Doctorate Studentship in Formulation Engineering at the University of Birmingham sponsored by the EPSRC (EP/G036713/1) and Johnson Matthey.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.jcat.2015.06.00

Is Extended Volume of External Beam Irradiation Beneficial in Post-esophagectomy High Risk Patients Receiving Combined Chemoradiation Therapy?

OBJECTIVE: To assess the value of extended volume irradiation with anastomotic coverage in high risk resected esophageal cancer patients. METHOD: A retrospective study was undertaken at LRCC from 1989-1999 for high risk resected esophageal cancer patients. Adjuvant treatments consisted of 4 cycles of chemotherapy (epirubicin/fluorouracil/cisplatin or cisplatin/fluorouracil), and local regional irradiation with or without coverage of the anastomotic site. Radiation dose ranged from 45-60Gy at 1.8-2.0 Gy/fraction given with initial anterior-posterior/posterior-anterior arrangement with either extended (with anastomotic coverage) or small (without anastomotic coverage) field followed by oblique fields for boost. RESULT: One hundred eighty-eight charts were reviewed. Seventy-two patients were eligible for post-resection chemoradiation therapy. Three patients had disease progression prior to therapy, and 69 patients were analyzed. There were 81% T3N1 and 13% T2N1. Thirty-four patients had margin involvements (radial 53%; proximal/distal 32%), 65% were adenocarcinoma and 33% were squamous carcinoma. Median followup was 23.6 months (3.4 - 78.4 months). Two year survival was 50%; 5yr 24%. Relapse rate was 62.3% and median time to relapse was 20 months. Recurrence locally to anastomosis or adjacent to anastomosis was 9/43(20.9%) with small field and 2/26(7.7%) with extended field. Of 31 patients with relapse outside anastomosis, 14/20(70%) relapsed locoregional/distal when treated with small field and 3/11(27%) relapsed locoregional/distal when treated with extended field (p=0.02). There was no excess treatment interruption or chronic gastrointestinal toxicity with extended field irradiation. CONCLUSION: There is significant decrease in locoregional/distal relapse with use of extended field in high risk resected esophageal cancer patients

A pivotal role for starch in the reconfiguration of 14C-partitioning and allocation in Arabidopsis thaliana under short-term abiotic stress.

Plant carbon status is optimized for normal growth but is affected by abiotic stress. Here, we used 14C-labeling to provide the first holistic picture of carbon use changes during short-term osmotic, salinity, and cold stress in Arabidopsis thaliana. This could inform on the early mechanisms plants use to survive adverse environment, which is important for efficient agricultural production. We found that carbon allocation from source to sinks, and partitioning into major metabolite pools in the source leaf, sink leaves and roots showed both conserved and divergent responses to the stresses examined. Carbohydrates changed under all abiotic stresses applied; plants re-partitioned 14C to maintain sugar levels under stress, primarily by reducing 14C into the storage compounds in the source leaf, and decreasing 14C into the pools used for growth processes in the roots. Salinity and cold increased 14C-flux into protein, but as the stress progressed, protein degradation increased to produce amino acids, presumably for osmoprotection. Our work also emphasized that stress regulated the carbon channeled into starch, and its metabolic turnover. These stress-induced changes in starch metabolism and sugar export in the source were partly accompanied by transcriptional alteration in the T6P/SnRK1 regulatory pathway that are normally activated by carbon starvation

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients

Reductions in mesophyll and guard cell photosynthesis impact on the control of stomatal responses to light and CO2

Transgenic antisense tobacco plants with a range of reductions in sedoheptulose-1,7-bisphosphatase (SBPase) activity were used to investigate the role of photosynthesis in stomatal opening responses. High resolution chlorophyll a fluorescence imaging showed that the quantum efficiency of photosystem II electron transport (Fq′/Fm′) was decreased similarly in both guard and mesophyll cells of the SBPase antisense plants compared to the wild-type plants. This demonstrated for the first time that photosynthetic operating efficiency in the guard cells responds to changes in the regeneration capacity of the Calvin cycle. The rate of stomatal opening in response to a 30 min, 10-fold step increase in red photon flux density in the leaves from the SBPase antisense plants was significantly greater than wild-type plants. Final stomatal conductance under red and mixed blue/red irradiance was greater in the antisense plants than in the wild-type control plants despite lower CO2 assimilation rates and higher internal CO2 concentrations. Increasing CO2 concentration resulted in a similar stomatal closing response in wild-type and antisense plants when measured in red light. However, in the antisense plants with small reductions in SBPase activity greater stomatal conductances were observed at all Ci levels. Together, these data suggest that the primary light-induced opening or CO2-dependent closing response of stomata is not dependent upon guard or mesophyll cell photosynthetic capacity, but that photosynthetic electron transport, or its end-products, regulate the control of stomatal responses to light and CO2. © 2008 The Author(s)

The response of Plantago major ssp pleiosperma to elevated CO2 is modulated by the formation of secondary shoots

The effect of elevated CO2 on the relative growth rate (RGR) of Plantago major ssp. pleiosperma was studied during the vegetative stage, in relation to plant development, by growing plants at 350 mu l l(-1) or at 700 mu l l(-1) CO2 in non-limiting nutrient solution with nitrate. To minimize interference by the accumulation of non-structural carbohydrates in the interpretation of results, RGR was expressed on a f. wt basis (RGR(FW)), as were all plant weight ratios. Stimulation of the RGR(FW) Of the whole plant by elevated CO2 was transient, and did not last longer than 8 d. At the same time a transient increase in root weight ratio (RWR) was observed. In order to investigate whether the transient effect of elevated CO2 on RGR(FW) was size-dependent, the data were plotted versus total f. wt (log(e) transformed). The transient period of stimulation of RGR(FW) and of RWR by elevated CO2 was still found, but in both CO2 treatments RGR(FW) decreased after a certain plant size had been reached. This size coincided with the stage at which secondary shoots started to develop, and was reached earlier in plants grown at elevated CO2. The RGR of these secondary shoots (RGR(see)) was Still increased when the period of whole plant stimulation of RGR(FW) had ended, indicating that the development of these new sinks took priority over a continuation of the stimulation of RWR. It is hypothesized that in this Plantago subspecies the response of the RGR(FW) of the whole plants to elevated CO2 is modulated by the formation of secondary shoots. Apparently, partitioning of the extra soluble carbohydrates at elevated CO2 to this tissue takes precedence over partitioning to the roots. resulting in a cessation of stimulation of plant RGR(FW) by elevated CO2.info:eu-repo/semantics/publishedVersio

Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina

Aims/hypothesis Referred to as CCN, the family of growth factors consisting of cystein-rich protein 61 (CYR61, also known as CCN1), connective tissue growth factor (CTGF, also known as CCN2), nephroblastoma overexpressed gene (NOV, also known as CCN3) and WNT1-inducible signalling pathway proteins 1, 2 and 3 (WISP1, -2 and -3; also known as CCN4, -5 and -6) affects cellular growth, differentiation, adhesion and locomotion in wound repair, fibrotic disorders, inflammation and angiogenesis. AGEs formed in the diabetic milieu affect the same processes, leading to diabetic complications including diabetic retinopathy. We hypothesised that pathological effects of AGEs in the diabetic retina are a consequence of AGE-induced alterations in CCN family expression. Materials and methods CCN gene expression levels were studied at the mRNA and protein level in retinas of control and diabetic rats using real-time quantitative PCR, western blotting and immunohistochemistry at 6 and 12 weeks of streptozotocin-induced diabetes in the presence or absence of aminoguanidine, an AGE inhibitor. In addition, C57BL/6 mice were repeatedly injected with exogenously formed AGE to establish whether AGE modulate retinal CCN growth factors in vivo. Results After 6 weeks of diabetes, Cyr61 expression levels were increased more than threefold. At 12 weeks of diabetes, Ctgf expression levels were increased twofold. Treatment with aminoguanidine inhibited Cyr61 and Ctgf expression in diabetic rats, with reductions of 31 and 36%, respectively, compared with untreated animals. Western blotting showed a twofold increase in CTGF production, which was prevented by aminoguanidine treatment. In mice infused with exogenous AGE, Cyr61 expression increased fourfold and Ctgf expression increased twofold in the retina. Conclusion/interpretation CTGF and CYR61 are downstream effectors of AGE in the diabetic retina, implicating them as possible targets for future intervention strategies against the development of diabetic retinopath