The influence of polymorbidity, revascularization, and wound therapy on the healing of arterial ulceration

Joerg Tautenhahn1, Ralf Lobmann2, Brigitte Koenig3, Zuhir Halloul1, Hans Lippert1, Thomas Buerger11Department of General, Visceral and Vascular Surgery; 2Department of Endocrinology and Metabolism; 3Institute for Medical Microbiology, Medical School, Otto-von-Guericke University, Magdeburg, GermanyObjective: An ulcer categorized as Fontaine’s stage IV represents a chronic wound, risk factor of arteriosclerosis, and co-morbidities which disturb wound healing. Our objective was to analyze wound healing and to assess potential factors affecting the healing process.Methods: 199 patients were included in this 5-year study. The significance levels were determined by chi-squared and log-rank tests. The calculation of patency rate followed the Kaplan-Meier method.Results: Mean age and co-morbidities did not differ from those in current epidemiological studies. Of the patients with ulcer latency of more than 13 weeks (up to one year), 40% required vascular surgery. Vascular surgery was not possible for 53 patients and they were treated conservatively. The amputation rate in the conservatively treated group was 37%, whereas in the revascularizated group it was only 16%. Ulcers in patients with revascularization healed in 92% of cases after 24 weeks. In contrast, we found a healing rate of only 40% in the conservatively treated group (p < 0.001). Revascularization appeared more often in diabetic patients (n = 110; p < 0.01) and the wound size and number of infections were elevated (p = 0.03). Among those treated conservatively, wound healing was decelerated (p = 0.01/0.02; χ² test).Conclusions: The success of revascularization, presence of diabetes mellitus, and wound treatment proved to be prognostic factors for wound healing in arterial ulcers.Keywords: arterial leg ulcer, wound management, risk factors, revascularizatio

Stakeholders' perspectives on the operationalisation of the ecosystem service concept : Results from 27 case studies

The ecosystem service (ES) concept is becoming mainstream in policy and planning, but operational influence on practice is seldom reported. Here, we report the practitioners' perspectives on the practical implementation of the ES concept in 27 case studies. A standardised anonymous survey (n = 246), was used, focusing on the science-practice interaction process, perceived impact and expected use of the case study assessments. Operationalisation of the concept was shown to achieve a gradual change in practices: 13% of the case studies reported a change in action (e.g. management or policy change), and a further 40% anticipated that a change would result from the work. To a large extent the impact was attributed to a well conducted science-practice interaction process (>70%). The main reported advantages of the concept included: increased concept awareness and communication; enhanced participation and collaboration; production of comprehensive science-based knowledge; and production of spatially referenced knowledge for input to planning (91% indicated they had acquired new knowledge). The limitations were mostly case-specific and centred on methodology, data, and challenges with result implementation. The survey highlighted the crucial role of communication, participation and collaboration across different stakeholders, to implement the ES concept and enhance the democratisation of nature and landscape planning. (C) 2017 Published by Elsevier B.V.Peer reviewe

It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods

Among cyclic nucleotide phosphodiesterases (PDEs), PDE6 is unique in serving as an effector enzyme in G protein-coupled signal transduction. In retinal rods and cones, PDE6 is membrane-bound and activated to hydrolyse its substrate, cGMP, by binding of two active G protein alpha-subunits (G alpha*). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction-diffusion simulations. G alpha* titration of membrane-bound PDE6 reveals a strong functional asymmetry of the enzyme with respect to the affinity of G alpha* for its two binding sites on membrane-bound PDE6 and the enzymatic activity of the intermediary 1 : 1 G alpha*. PDE6 complex. Employing cGMP and its 8-bromo analogue as substrates, we find that G alpha*. PDE6 forms with high affinity but has virtually no cGMP hydrolytic activity. To fully activate PDE6, it takes a second copy of G alpha* which binds with lower affinity, forming G alpha*. PDE6. G alpha*. Reaction-diffusion simulations show that the functional asymmetry of membrane-bound PDE6 constitutes a coincidence switch and explains the lack of G protein-related noise in visual signal transduction. The high local concentration of G alpha* generated by a light-activated rhodopsin molecule efficiently activates PDE6, whereas the low density of spontaneously activated G alpha* fails to activate the effector enzyme

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1 alpha Axis in the Offspring of Obese Mothers

Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ss-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-gamma-coactivator-1 alpha (PGC-1 alpha)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1 alpha-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions

Impact of TSPO Receptor Polymorphism on [18F]GE-180 Binding in Healthy Brain and Pseudo-Reference Regions of Neurooncological and Neurodegenerative Disorders

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium- and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [18F]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [18F]GE-180 binding in a healthy brain and in pseudo-reference tissue in neuro-oncological and neurodegenerative diseases. Standardized uptake values (SUVs) of [18F]GE-180-PET were assessed using a manually drawn region of interest in the frontoparietal and cerebellar hemispheres. The SUVs were compared between the LABs, MABs and HABs in control, glioma, four-repeat tauopathy (4RT) and Alzheimer’s disease (AD) subjects. Second, the SUVs were compared between the patients and controls within their rs6971-subgroups. After excluding patients with prior therapy, 24 LABs (7 control, 5 glioma, 6 4RT and 6 AD) were analyzed. Age- and sex-matched MABs (n = 38) and HABs (n = 50) were selected. The LABs had lower frontoparietal and cerebellar SUVs when compared with the MABs and HABs, but no significant difference was observed between the MABs and HABs. Within each rs6971 group, no SUV difference between the patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [18F]GE-180 quantification, revealing lower binding in the LABs when compared to the MABs and HABs. The frontoparietal and cerebellar ROIs were successfully validated as pseudo-reference regions

Impact of TSPO Receptor Polymorphism on [F-18]GE-180 Binding in Healthy Brain and Pseudo-Reference Regions of Neurooncological and Neurodegenerative Disorders

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium- and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [F-18]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [F-18]GE-180 binding in a healthy brain and in pseudo-reference tissue in neuro-oncological and neurodegenerative diseases. Standardized uptake values (SUVs) of [F-18]GE-180-PET were assessed using a manually drawn region of interest in the frontoparietal and cerebellar hemispheres. The SUVs were compared between the LABs, MABs and HABs in control, glioma, four-repeat tauopathy (4RT) and Alzheimer's disease (AD) subjects. Second, the SUVs were compared between the patients and controls within their rs6971-subgroups. After excluding patients with prior therapy, 24 LABs (7 control, 5 glioma, 6 4RT and 6 AD) were analyzed. Age- and sex-matched MABs (n = 38) and HABs (n = 50) were selected. The LABs had lower frontoparietal and cerebellar SUVs when compared with the MABs and HABs, but no significant difference was observed between the MABs and HABs. Within each rs6971 group, no SUV difference between the patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [F-18]GE-180 quantification, revealing lower binding in the LABs when compared to the MABs and HABs. The frontoparietal and cerebellar ROIs were successfully validated as pseudo-reference regions

Impact of TSPO Receptor Polymorphism on [18F]GE-180 Binding in Healthy Brain and Pseudo-Reference Regions of Neurooncological and Neurodegenerative Disorders

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium- and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [F-18]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [F-18]GE-180 binding in a healthy brain and in pseudo-reference tissue in neuro-oncological and neurodegenerative diseases. Standardized uptake values (SUVs) of [F-18]GE-180-PET were assessed using a manually drawn region of interest in the frontoparietal and cerebellar hemispheres. The SUVs were compared between the LABs, MABs and HABs in control, glioma, four-repeat tauopathy (4RT) and Alzheimer's disease (AD) subjects. Second, the SUVs were compared between the patients and controls within their rs6971-subgroups. After excluding patients with prior therapy, 24 LABs (7 control, 5 glioma, 6 4RT and 6 AD) were analyzed. Age- and sex-matched MABs (n = 38) and HABs (n = 50) were selected. The LABs had lower frontoparietal and cerebellar SUVs when compared with the MABs and HABs, but no significant difference was observed between the MABs and HABs. Within each rs6971 group, no SUV difference between the patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [F-18]GE-180 quantification, revealing lower binding in the LABs when compared to the MABs and HABs. The frontoparietal and cerebellar ROIs were successfully validated as pseudo-reference regions

X-ray crystallography study on ribosome recycling: the mechanism of binding and action of RRF on the 50S ribosomal subunit

This study presents the crystal structure of domain I of the Escherichia coli ribosome recycling factor (RRF) bound to the Deinococcus radiodurans 50S subunit. The orientation of RRF is consistent with the position determined on a 70S-RRF complex by cryoelectron microscopy (cryo-EM). Alignment, however, requires a rotation of 7° and a shift of the cryo-EM RRF by a complete turn of an α-helix, redefining the contacts established with ribosomal components. At 3.3 Å resolution, RRF is seen to interact exclusively with ribosomal elements associated with tRNA binding and/or translocation. Furthermore, these results now provide a high-resolution structural description of the conformational changes that were suspected to occur on the 70S-RRF complex, which has implications for the synergistic action of RRF with elongation factor G (EF-G). Specifically, the tip of the universal bridge element H69 is shifted by 20 Å toward h44 of the 30S subunit, suggesting that RRF primes the intersubunit bridge B2a for the action of EF-G. Collectively, our data enable a model to be proposed for the dual action of EF-G and RRF during ribosome recycling